Porous cellulose aggregate and molding composition thereof

ABSTRACT

A porous cellulose aggregate characterized by having a secondary aggregate structure resulting from aggregation of primary cellulose particles, having a pore volume within a particle of 0.265 to 2.625 cm 3 /g, containing I-type crystals and having an average particle size of over 30 to 250 μm, a specific surface area of 0.1 to less than 20 m 2 /g, a repose angle of 25° to less than 44° and a swelling degree of 5% or more, and characterized by having the property of disintegrating in water.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/918,979, filed on Oct. 22, 2077, which claims the benefit under 35U.S.C. Section 371, of PCT International Application No.PCT/JP2006/308414, filed Apr. 21, 2006 and Japanese Application No.2005-124477, filed Apr. 22, 2005, the contents of which are incorporatedherein by reference.

TECHNICAL FIELD

The present invention relates to a porous cellulose aggregate that isuseful mainly as an excipient in the field of chemical engineering, inparticular, of pharmaceuticals and of foods, and a compacting (molding)composition thereof.

BACKGROUND ART

In the fields of pharmaceuticals, foods and other chemical engineeringand the like, it has been a general practice conventionally to prepare amolded body containing an active ingredient using cellulose particlessuch as crystalline cellulose, cellulose powder and the like as anexcipient, and for these cellulose particles, good compactibility,fluidity and disintegration property are required.

Patent Document 1 describes a porous cellulose aggregate (correspondingto Comparative Example 15-17) having a secondary aggregate structureformed by aggregation of primary cellulose particles, the aggregatehaving a pore volume within a particle of 0.265 cm³/g to 2.625 cm³/g,containing type I crystals, and having an average particle size of morethan 30 μm and 250 μm or less, a specific surface area of 1.3-20 m²/g, arepose angle of 25° or more and less than 44° and properties todisintegrate in water, and a method for producing the aforementionedporous cellulose aggregate comprising a step of drying a dispersioncontaining two or more groups of primary cellulose particles having adifferent average particle size and a liquid medium wherein thecellulose dispersion particles have an average particle size of 1 to 110μm. Since the aforementioned porous cellulose aggregate of the PatentDocument requires two or more groups of primary cellulose particleshaving a different average particle size, different primary celluloseparticles prepared by two processes such as grinding dried acidinsoluble residue of commercially available pulp and the like have to bemixed as described in Example of the Patent Document. On the other handthe porous cellulose particles of the present invention can be obtainedadvantageously with a single process without going through a process ofgrinding or the like. The porous cellulose aggregates of the presentinvention can be obtained by a single process by making the primarycellulose particles to have a specified range of average width andaverage thickness and by making flexible, thereby promoting entanglementof primary cellulose particles without being limited by the major axisof the primary cellulose particles, in other words by giving selfaggregation ability thereto, and are clearly different from thatdescribed in the Patent Document in terms of the production method. Inaddition, because the pore size of the secondary aggregate structure ofthe porous cellulose particles according to the Patent Document issmaller than that of the porous cellulose aggregates of the presentinvention, and the swelling degree is lower in water, the disintegrationproperty is sometimes not sufficient for making tablets for aformulation that severely requires disintegration property in the caseof drugs which is insoluble in water, and even in the case of solubledrugs, when a water repellent additives such as magnesium stearate andthe like has to be added to avoid problems in tablet pressing such assticking and the like. We have investigated in detail the particlestructure which controls disintegration property, and as a resultconfirmed again that the cellulose particles having a high swellingproperty have a high disintegration property, and we realized that forconventional cellulose powder, if the swelling property is high, thecompactibility is not sufficient, and conversely if the compactibilityis high, the swelling property is low. That is, no cellulose powderhaving both a high compactibility and high swelling property has beenknown. We searched for a method to make the particles porous whilekeeping the pore diameter of porous cellulose particles as large aspossible and have managed to solve the aforementioned problem. That is,we found that excess aggregation can be controlled, and the inside ofthe particles can be made porous while keeping the pore diameter largeby using primary cellulose particles having a specified range of averagewidth and average thickness and giving self-aggregation ability thereto.For the porous cellulose aggregates of Patent Document 1, it isdescribed that when two or more groups of cellulose particles havingdifferent particle size are mixed, and the cellulose dispersion isdried, the dispersed cellulose particles having a small averageparticles size enter between the dispersed cellulose particle componentshaving a large average particle size, and for this reason an excessaggregation of the dispersed cellulose particles having the largeraverage particle size is inhibited, and a large pore volume is createdin the secondary aggregate structure. However, since tight aggregationis formed among two or more groups of cellulose having different averageparticle size, the pore diameter of the porous cellulose aggregatesobtained by the method particularly disclosed in the Example wasmeasured to be small, about 1.5 μm. Since the porous cellulose aggregateof the present invention uses the single primary cellulose particles,they are not aggregated as tightly as the porous cellulose aggregate ofthe Patent Document and they are different in having a minimum 3 μm porediameter. For the size of pore diameter, the Patent Document describesthat a clear peak can be recognized in the range of 0.1-10 μm and themedian pore diameter, which is a peak top of the pore distribution andclosely related to water permeability into the particles, is preferably0.3 μm or larger, and that although a larger median pore diameter isbetter, it is at most 5 μm considering its distribution. It is describedthat with a larger median pore diameter, there is better disintegrationproperty, but it is speculated that in practice it is difficult toobtain a large median pore diameter of 3 μm or larger by the productionmethod according to the Patent Document. The porous cellulose aggregatesof the present invention has an advantage that porous celluloseaggregates having a large median pore diameter of 3 μm or above, whichcan not be obtained by the production method of the Patent Document, canbe prepared by a single step without requiring mixing of the differentprimary cellulose particles prepared through two steps.

Patent Document 2 describes porous cellulose particles (corresponding toComparative 6 of the present application) having a crystal structuretype I, having pores of diameter of 0.1 μm or above and a porous rate of20% or above and containing 90% by weight or above of a fraction with350 mesh and above, which is obtained by mixing cellulose particles withthe third component such as a crystalline compound or the like that isinsoluble or hard to be soluble in water but soluble in an organicsolvent, by granulating and drying the mixture using water or a watersoluble organic solvent and then extracting/removing the third componentwith an organic solvent. The porous cellulose particles described inthis document is entirely different from the porous cellulose aggregatesof the present invention in the particle structure, because the primarycellulose particles form such a homogeneous continuous film-like tightstrong cellulose wall structure that the boundaries of the particlesbecome unclear. Although the cellulose particle in Patent Document 2 issuperior in its fluidity, the tight continuous cellulose wall isimpermeable to water, so that the cellulose particle was notdisintegrated in water, and sometimes the rapid release of an activeingredient was impeded. Further, the cellulose particle of PatentDocument 2 is poor in its plastic deformation and has insufficientcompactibility while the cellulose is compressed, and furthermore sincean organic solvent and a third component, which is a crystallinecompound soluble in the organic solvent, are used during the productionprocess, not only the production cost is high but also the activeingredient can be inactivated. Thus it is insufficient to be used stablyas an excipient.

Patent Document 3 describes porous micro-cellulose particles(corresponding to Comparative Example 7 of the present application)having a porous structure with crystal structure type I, a specificsurface area of 20 m²/g of above and a pore volume of 0.3 cm³ or abovefor pores with diameter 0.01 μm or larger, and having an averageparticle size of at most 100 μm, obtained by granulating and drying fineparticle natural cellulose dispersed in an organic solvent usingspray-dry method. These micro-cellulose particles also have theaforementioned cellulose wall structure and are entirely different fromthe porous cellulose aggregates of the present invention in the particlestructure. Further, the pore volume itself of the cellulose particles ofPatent Document 3 is large, but since the particle structure isdifferent from that of the porous cellulose aggregates of the presentinvention, water permeation into the particles is difficult, and thereis a problem of the inferior disintegration property. In addition, sincean organic solvent is used for these porous cellulose aggregateparticles during the production process, not only is the production costhigh but also the active ingredient can be inactivated because thespecific surface area is too large and the interaction between theactive ingredient and water is promoted. Thus it is insufficient to beused stably as an excipient.

Patent Document 4 describes cellulose powder (corresponding toComparative Example 8 of the present application) having an averagedegree of polymerization of 150-375, apparent specific volume of1.84-8.92 cm³/g, a particle size of 300 μm or less as cellulose powderhaving a good compactibility and disintegration property.

Patent Document 5 describes micro-crystalline cellulose aggregates(corresponding to Comparative Example 9 of the present application)having an average degree of polymerization of 60-375, apparent specificvolume of 1.6-3.1 cm³/g, apparent tapping specific volume of 1.4 cm³/gor above, a repose angle of 35-42°, and containing 2-80% by weight ofcomponent of 200 mesh or above. The cellulose powder obtained accordingto Examples of these Patent Documents has a small intraparticular porevolume according to the measurement result of pore distribution usingmercury porosimetry and the pore structure is entirely different fromthat of the present invention which is formed intentionally. For thatreason, these cellulose powders have a small specific surface area of0.6-1.2 cm³ and poor compactibility. These publications disclose thecontrol of the compactibility, fluidity and disintegration property ofcellulose particles by adjusting the apparent specific volume, but therewere problems that in the range of relatively small apparent specificvolume of 2.0-2.9 cm³/g, the fluidity and disintegration property weregood but the compactibility was unsatisfactory, while with largerapparent specific volume of 3.0-3.2 cm³/g, the compactibility was goodbut the fluidity and disintegration property were poor.

Patent Document 6 describes β-1,4-glucan powder (corresponding toComparative Example 1 of the present application) as cellulose powderhaving good compactibility having an average particle size of at most 30μm and a specific surface area of 1.3 m²/g. The β-1,4-glucan powderdescribed in the document does not have the secondary aggregatestructure, and individual primary particles exist singly. Although thisglucan powder has good compactibility, it has problems that thedisintegration property is poor and the fluidity is inferior due to thesmall average particle size.

Patent Document 7 describes a cellulose powder (corresponding toComparative Example 10 of the present application) having an averagedegree of polymerization of 100-375, an acetic acid retention rate of280% or above, Kawakita formula (P*V0/(V0−V)=1/a*b+P/a) wherein a is0.85-0.90, b is 0.05-0.10, an apparent specific volume of 4.0-6.0 cm³/g,substantially no particles of 355 μm or larger, and an average particlesize of 30-120 μm as a cellulose powder having good compactibility anddisintegration property obtained by hydrolyzing a cellulose-likesubstance. The cellulose powder obtained by the method of Exampledescribed in that document has also a small pore volume within aparticle according to the measurement result of pore distribution usingthe mercury porosimetry and thus the pore structure is entirelydifferent from the intentionally formed pore structure of the presentinvention. Although the cellulose powder of Patent Document 7 isdescribed to have good compression compactibility and disintegrationproperty, the best balanced Example that is disclosed specifically ismeasured to have a repose angle of over 55° and the fluidity is notsatisfactory enough. There was a problem that in formulations, in whichan active ingredient having poor fluidity was used in large proportion,the variation coefficient of tablet weight was larger therebyinfluencing uniformity of the drug content. Further, when compacting(molding) was performed under high pressure using the cellulose powderaccording to the document, a high hardness can be obtained but there wasa problem of delayed disintegration because there is no intentionallyformed intraparticular pore, and water permeability to inside of theparticle was low.

Patent Document 8 describes a crystalline cellulose (corresponding toComparative Example of 11 of the present application) as the cellulosepowder having good compactibility, disintegration property and fluidity,which has an average degree of polymerization of 100-375, and in whichthe particles that pass through a 75 μm sieve and are retained on a 38μm sieve occupy 70% or more of the total weight, and an average majoraxis and minor axis ratio of the particles is 2.0 or higher.

Patent Document 9 describes a cellulose powder (corresponding toComparative Example of 2-4 of the present application) as the cellulosehaving good compactibility, disintegration property and fluidity, havingan average degree of polymerization of 150-450, an average L/D (ratio ofmajor axis/minor axis) of 2.0-4.5 for particles of 75 μm or less, anaverage particle size of 20-250 μm, an apparent specific volume of4.0-7.0 cm³/g, and a repose angle of 54° or less and a specific surfacearea of 0.5-4 m²/g. Since the pore volume within a particle of thecellulose powders described in these publications, similar to the casesdescribed above, measured by the mercury porosimetry is small, thecellulose have entirely different pore structure from the intentionallyformed pore structure of the present invention. The cellulose powdersdescribed in these publications give a high hardness to a molded body byelongating the shape of particles, but because they have an elongatedshape, the apparent specific volume becomes larger, and the higher thecompactibility, the fluidity decreases. Among the cellulose powders inExamples described in these publications, the one having the bestfluidity was measured to have a repose angle of 44°. For example, whencontinuous compression was performed at high speed in a formulation inwhich an active ingredient having poor fluidity was mixed in a largeproportion, the variation coefficient of tablet weight was gettinglarger, thereby influencing uniformity of the drug content, and thussatisfactory result was not obtained in terms of fluidity. Further, whencompacting (molding) was performed under high pressure using thecellulose powder according to these publications, high hardness can beachieved but there was a problem of delayed disintegration because therewas no intentionally formed intraparticular pore, and water permeabilityto the inside of particle was low.

Patent Document 10 describes a cellulose powder (corresponding toComparative Example 14 of the present application) having an averagedegree of polymerization of 150-450, an average particle size 30-250 μmapparent specific volume of over 7 cm³/g and a holding capacity ofpolyethylene glycol with a molecular weight of 400 of 190% or more. Thecellulose powder of this document does not hold a secondary aggregatestructure, and primary cellulose particles exist substantially as asinglet. Also, the intraparticular pore volume measured by the mercuryporositometry is small and the cellulose powder has an entirelydifferent pore structure from the intentionally formed pore structure ofthe present invention. Further, when the apparent specific volume islarge, the fluidity is greatly impaired, and the repose angle of thebest cellulose powder in terms of fluidity according to this documentwas measured to be 50°. For example, when continuous compacting(molding) was performed at high speed in a formulation in which anactive ingredient having poor fluidity was mixed in a large proportion,the variation coefficient of tablet weight was increased, therebyinfluencing uniformity of the drug content, and thus satisfactory resultwas not obtained in terms of fluidity. Further, when compacting(molding) was performed under high pressure using the cellulose powderaccording to the document, high hardness can be achieved but there was aproblem of delayed disintegration because there was no intentionallyformed intraparticular pores, and water permeability to the inside ofparticle was low.

In addition, the average particle size of the dispersed celluloseparticles in the cellulose dispersion must be 50 μm or larger toincrease the apparent specific volume, but the average particle size ofthe dispersed cellulose particles of the present invention is obtainedat 10 μm or larger and less than 50 μm, which is quite different interms of the production method.

In the range of 2.3-6.4 cm³/g of the apparent specific volume for thecellulose powders described in these Patent Documents 6-9, and in therange of over 7 cm³/g of the apparent specific volume for the cellulosepowders described in Patent Document 10, sufficient compactibility wasobtained in each case but there was a problem that the fluidity anddisintegration property were deteriorated.

Patent Document 11 describes pharmacologically inert round shaped seedcore containing 10-70% of a crystalline cellulose having an averagedegree of polymerization of 60-375 and 10-90% of a water solubleadditive as cellulose particles having good fluidity. Further, PatentDocument 12 describes a pharmacologically inert round shaped seed core(corresponding to Comparative Example 12 of the present application)containing 50% or more of a crystalline cellulose having a waterabsorbing capacity of 0.5-1.5 ml/g, roundness of 0.7 or higher, anapparent tapping specific volume of 0.65 g/ml or higher, a friability of1% or less and an average degree of polymerization of 60-375, whereindistilled water is added to powder containing crystalline cellulose at50% or more while mixing using a mixer granulator and kneaded to preparethe round shaped seed core. Patent Document 13 describesmicrocrystalline cellulose particles having a loose bulk density of atleast 0.4 g/cm³ (2.5 cm³/g in apparent specific volume), sphericalshape, an average particle size of 2-35 μm and a smooth surface, whereinthe microcrystalline cellulose particles is prepared by mechanicallyreducing the particle size of hydrolyzed cellulose particles and byspray-drying. Patent Document 14 describes cellulose system particles(corresponding to Comparative Example 13 of the present application)containing 10% or more of the crystalline cellulose having an averagedegree of polymerization of 60-350, and having an apparent tappingspecific volume of 0.60-0.95 g/ml, roundness of 0.7 or higher, a shapecoefficient of 1.10-1.50, and an average particle size of 10-400 μm,wherein the crystalline cellulose is obtained by hydrolyzing a cellulosematerial to an average degree of polymerization of 60-350, then grindingthe result mechanically to the average particle size of 15 μm, and thendrying the dispersion containing thus obtained crystalline cellulose ina shape of liquid droplets.

The cellulose particles described in these documents do not form asecondary aggregate structure, and the celluloses obtained by the methodof Examples described in Patent Documents have an apparent specificvolume of 2.5 cm³/g or lower, nearly spherical shape and good fluiditybut are poor in compression compactibility, and under the commonly usedcompression pressure of 10-20 MPa, a molded body which has sufficienthardness for practical use can not be made.

As described above, for cellulose particles of conventional arts,compactibility, fluidity and disintegration property have been mutuallycontradictory characteristics, and it has been hoped to obtain celluloseparticles having these characteristics in good balance.

On the other hand, since the cellulose particles described in PatentDocuments 4-9, and 11-14 do not have intraparticular pores that areintentionally formed, and pore volume within a particle is small, almostno active ingredient can be held in the particles and therefore therehave been problems of liquid components bleeding out in compressioncompacting (molding) and problems in tablet press operation. Also, thecellulose particles described in Patent Document 2 and 3 haveintraparticular pores, but the pore diameter is small, and therefore itis difficult for water to permeate into the dense and continuouscellulose wall, which imposes problems that the cellulose particle doesnot disintegrate in water and quick release of an active ingredient ishindered. The cellulose particles described in Patent Document 10 has anapparent specific volume that is too big, and especially in high speedcompression compacting (molding) they sometimes cannot be practicallyused because of the their fluidity and disintegration property.

Furthermore, since these cellulose particles do not have intraparticularpores that are intentionally formed, and the pore volume within aparticle is small, almost no active ingredient can be held in theparticles, and thus they have a shortcoming that in solid formulation ofan active ingredient that is hard to be soluble in water, theformulation can not be practically used due to slow elution of theactive ingredient, unless complicated processes are performed such astemporary granulation with water or an organic solvent, drying and thelike. They also have a shortcoming that in solid formulation of anactive ingredient that tends to sublimate, the active ingredientre-crystallizes during storage, ruining their commercial value.

The active ingredient in a solid formulation for oral administration iseluted from the formulation to the body fluid in the digestive tract,absorbed from the digestive tract, enters into the blood circulation andexpresses the drug effect. Since the active ingredient that is hard tobe soluble in water is poorly eluted, sometimes it is excreted out ofthe body before all the administered active ingredient is eluted andfull effect is not expressed. The ratio of the total amount of activeingredient entering into the blood circulation to the administeredamount of active ingredient is generally known as bioavailability, andto improve bioavailability and the rapid action of active ingredient,various methods have been investigated up until now for improving theelution of hardly-soluble active ingredients.

Patent Document 15 describes a method for grinding an active ingredientthat is hard to be soluble in water and β-1,4-glucan powder together.This method needs a long time for grinding treatment until crystallinecharacteristics of β-1,4-glucan powder are lost, and also powerful shearmust be applied continuously for a long time using a roll mixer, thuscreating a problem of poor efficiency in the actual production process.Further, β-1,4-glucan powder that has lost the crystallinecharacteristics has a problem of poor compression compactibility.

For a solid formulation for oral administration prepared by the directpress method from a main drug that is hard to be soluble in water,Patent Document 16 describes a method for increasing the disintegrationof the tablet and the rate of elution of the main drug by increasing thehardness of the tablet and decreasing the variation of the main drugcontent by adding β-1,4-glucan, a disintegrator and a surfactant. Thisdocument describes no intraparticular pores, and it is not known at allto improve water solubility of a drug by mixing an active ingredientthat is hard to be soluble in water and a porous cellulose aggregate.Furthermore, since a surfactant has to be added to facilitate theelution of the active ingredient that is hard to be soluble in water,there is a problem that when this solid formulation was administered,the surfactant caused inflammation of the mucus membrane of thedigestive tract.

Further, Patent Document 17 describes that when tablets are produced bythe wet press method using a main drug that is hard to be soluble inwater and β-1,4-glucan through the steps of powder mixing, kneading,granulation and drying, tablets having a high tablet hardness, a shortdisintegration time and a fast elution rate of the main drug can beproduced by adding a water soluble polymer solution. Also, this documentdescribes no porous cellulose particle having large intraparticularpores, and it is not known at all to improve water solubility of a drugby mixing an active ingredient that is hard to be soluble in water and aporous cellulose aggregate. Still further in such a method, many stepsare essential for drying and there are problems of the cost related tothe equipment, and that the energy cost for drying is high. Also, thereare problems that this method cannot be applied to an active ingredientinactivated by heat and the like problems.

Patent Document 18 describes a method for improving the elution of adrug by mixing a hardly-soluble drug with porous structured celluloseparticles having a particular specific surface area and a pore volume,which is obtained by granulating and drying fine particle like naturalcellulose dispersed in an organic solvent by the spray dry method, andabsorbing thereto by sublimation. Since the porous cellulose particlesdescribed in that document have a high specific surface area and a largepore volume within a particle, the improvement of elution is sure to beobserved when the hardly-soluble active ingredient is absorbed bysublimation. However, Example of this Patent Document uses celluloseparticles having excessively high specific surface area and the activeingredient absorbed on the surface by sublimation is amorphous andtherefore there is a problem of storage stability because during thestorage a part of the active ingredient is crystallized and the elutionrate is changed, and in a tightly bound compacting composition such as atablet, there is a shortcoming that the elution of the active ingredientis slow because its disintegration is impeded due to the poordisintegration property.

A sublimatable active ingredient has a problem of bleeding out of asolid formulation during storage, and to prevent this from happening,many of these solid formulations are film coated or sugar coated.However, even with such treatments, there are problems that the activeingredient bleeding out of the formulation through the film layer causeslow uniformity of the active ingredient content in the formulation, theactive ingredient attached to the surface of the formulation givesirritating smell when taking the formulation or re-crystallizing in apreserving container such as a vial greatly reduces the commercialvalue. When the coating treatment is not performed on the formulation,the sublimation-re-crystallization is more pronounced than when thecoating treatment is performed.

As already described above, in Patent Document 18 cellulose particleshaving excessively high specific surface area was used, and since theactive ingredient absorbed by sublimation on the surface was amorphous,there was a problem of poor storage stability of the active ingredient,and in a tightly bound compacting composition such as a tablet, therewas a shortcoming that the elution of the active ingredient was slowbecause its disintegration was impeded due to the poor disintegrationproperty.

Also, as a method for preventing the re-crystallization caused bysublimation of ibuprofen in solid formulation, Patent Document 19describes a method for preserving ibuprofen containing solid formulationtogether with 1 or plurality of stabilizers selected from the groupconsisting of polyvinyl pyrrolidone, magnesium oxide and sodiumbicarbonate in a closed container such as a vial. Using this method thedeposition of crystals to the original closed container that haspreserved the formulation and the irritating smell of the formulationare surely improved, but polyvinyl pyrrolidone, magnesium oxide, sodiumcarbonate and the like have to be placed in the container as separateformulations, making the process more complicated, and thus this isentirely different from a single formulation which is madesublimation-proof by adding to the formulation a porous cellulose suchas the formulation of the present invention containing a sublimatableactive ingredient.

In the past, a composition containing an active ingredient that wasoily, liquid or semi solid at normal temperature had problems comparedto a solid active ingredient that it is especially prone to tabletpressing problems due to the liquid component bleeding out from theformulation, spots of the liquid component are produced on the surfaceof the formulation, and in the case of granular formulation, inferiorfluidity occurred. These problems not only markedly lower the quality ofthe product but also cause the low uniformity of the concentration andeffect of the active ingredient, and thus improving these problems is avery important task.

In the production of tablets, Patent Document 20-31 describe a methodfor retaining an active ingredient that is liquid/semi solid at normaltemperature to an absorption carrier as it is, or holding an activeingredient dissolved, emulsified or suspended in water, organic solvent,oil, aqueous polymer or surfactant to an absorption carrier, and thencompression compacting dried powder or granules obtained after a dryingstep. However, by the methods of these Patent Documents, the activeingredient that is liquid or semisolid at normal temperature effuses outat the time of compression, causing tablet pressing troubles, andsometimes satisfactory compression molded body may not be obtained.Also, for cellulose particles these Patent Documents do not describe apore volume within a particle, and it is not known that when the activeingredient that is liquid or semisolid at room temperature iscompressed, the addition of the porous cellulose particles of thepresent invention having a large pore volume within a particle preventsbleeding out by the porous cellulose aggregate holding the activeingredient that is liquid or semisolid inside of the particles and makespreparation of solid formulations such as powder, granules, tablets andthe like easier. Still further, in the method described in PatentDocument 20-31 many steps are essential for drying and there areproblems that the cost related to the equipment, and the energy cost fordrying is high.

-   Patent Document 1: International Patent Application No. 2005/073286    Pamphlet-   Patent Document 2: JP-A-1-272643-   Patent Document 3: JP-A-2-84401-   Patent Document 4: JP-B-40-26274 (CA 699100 A)-   Patent Document 5: JP-A-53-127553 (U.S. Pat. No. 4,159,345 A)-   Patent Document 6: JP-A-63-267731-   Patent Document 7: JP-A-6-316535 (U.S. Pat. No. 5,574,150)-   Patent Document 8: JP-A-11-152233-   Patent Document 9: International Patent Application No. 02/02643    Pamphlet (US20040053887 A1)-   Patent Document 10: International Patent Application No. 2004/106416    Pamphlet (EP1634908)-   Patent Document 11: JP-A-4-283520-   Patent Document 12: JP-A-7-173050 (U.S. Pat. No. 5,505,983),-   U.S. Pat. No. 5,384,130)-   Patent Document 13: JP-A-7-507692 (U.S. Pat. No. 5,976,600 A)-   Patent Document 14: International Patent Application No. 02/36168    Pamphlet (US20040043964 A1)-   Patent Document 15: JP-B-53-22138 (U.S. Pat. No. 4,036,990 A)-   Patent Document 16: JP-A-53-044617-   Patent Document 17: JP-A-54-052718-   Patent Document 18: JP-A-03-264537-   Patent Document 19: JP-A-08-193027-   Patent Document 20: JP-A-56-7713-   Patent Document 21: JP-A-60-25919-   Patent Document 22: JP-A-61-207341-   Patent Document 23: JP-A-11-193229 (EP972513 B1)-   Patent Document 24: JP-A-11-35487-   Patent Document 25: JP-A-2000-16934-   Patent Document 26: JP-A-2000-247869-   Patent Document 27: JP-A-2001-181195-   Patent Document 28: JP-A-2001-316248-   Patent Document 29: JP-A-2002-534455 (U.S. Pat. No. 6,630,150)-   Patent Document 30: JP-A-2003-161-   Patent Document 31: JP-A-2003-55219

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The problem of the present invention is to provide an excipient having agood compactibility, fluidity and disintegration property used forproducing a molded body containing various active ingredients by makingcellulose particles into a porous cellulose aggregate having a specificpore volume.

Means for Solving the Problem

The present inventors, to solve the aforementioned problem, controlledthe particle structure of a cellulose aggregate, expressed a secondaryaggregate structure, increased an intraparticular pore volume of thecellulose aggregate and controlled the powder properties of thecellulose aggregate to a specific range to complete the presentinvention.

That is, the present invention is as follows.

(1) A porous cellulose aggregate having a secondary aggregate structureformed by aggregation of primary cellulose particles, a pore volumewithin a particle of 0.265 cm³/g-2.625 cm³/g, containing type Icrystals, and having an average particle size of more than 30 μm and 250μm or less, a specific surface area of 0.1 m²/g or more and less than 20m²/g, a repose angle of 25° or more and less than 44°, a swelling degreeof 5% or more, and properties to disintegrate in water.(2) The porous cellulose aggregate according to (1), in which acylinder-like molded body having a hardness of 70-160 N and a reposeangle of over 36° and less than 44° is obtained by weighing 0.5 g of theaforementioned porous cellulose aggregate and placing it in a die,compressing it with a round flat punch with a diameter of 1.1 cm until apressure of 10 MPa is attained, and holding at the target pressure for10 seconds.(3) The porous cellulose aggregate according to (1), in which thecylinder-like molded body having a hardness of 60-100 N and a reposeangle of 25° or larger and 36° or smaller is obtained by weighing 0.5 gof the aforementioned porous cellulose aggregate and placing in a die,compressing with a round flat punch with a diameter of 1.1 cm until apressure of 10 MPa is attained, and holding at the target pressure for10 seconds.(4) The porous cellulose aggregate according to any one of (1)-(3) thatcan be obtained by a production method including: a step of obtaining adispersion (hereinafter may also be designated as a cellulosedispersion) containing a natural cellulose material in which primarycellulose particles have an average particle size of 10 μm or larger andless than 50 μm, average width of 2-30 μm and average thickness of 0.5-5μm, and a step of drying thus obtained cellulose dispersion.(5) The porous cellulose aggregate according to (4), in which theaforementioned cellulose dispersion contains 10% by weight or less ofparticles that are not sedimented at a centrifugal condition ofcentrifugal force of 4900 m/s².(6) A method for producing the porous cellulose aggregate according toany one of (1)-(3) including: a step of obtaining a dispersion(hereinafter may also be designated as a cellulose dispersion)containing a natural cellulose material in which primary celluloseparticles have an average particle size of 10 μm or larger and less than50 μm, average width of 2-30 μm and average thickness of 0.5-5 μm, and astep of drying thus obtained cellulose dispersion.(7) The method according to (6), in which the aforementioned cellulosedispersion contains 10% by weight or less of particles that is notsedimented at a centrifugal condition of centrifugal force of 4900 m/s².(8) The method according to (6), in which shearing and stirring areperformed during a step of subjecting the aforementioned naturalcellulose substance to a mechanical treatment such as crushing, grindingor the like or a chemical treatment such as hydrolysis or the like, or acombination of both treatments, or stirring is performed during a stepafter these treatments.(9) The method according to (6), in which shearing and stirring areperformed during a step of subjecting the aforementioned naturalcellulose substance to a mechanical treatment such as crushing, grindingor the like and then during the step of hydrolysis.(10) The method according to (6), in which the aforementioned naturalcellulose substance is subjected to stirring during the step ofhydrolysis, or during the step thereafter.(11) The method according to (8), in which the aforementioned cellulosedispersion contains 10% by weight or less of particles that are notsedimented at a centrifugal condition of centrifugal force of 4900 m/s².(12) The method according to (9), in which the aforementioned cellulosedispersion contains 10% by weight or less of particles that are notsedimented at a centrifugal condition of centrifugal force of 4900 m/s².(13) The method according to (10), in which the aforementioned cellulosedispersion contains 10% by weight or less of particles that are notsedimented at a centrifugal condition of centrifugal force of 4900 m/s².(14) The porous cellulose aggregate according to (4), in which theaforementioned natural cellulose substance is a wood pulp having alevel-off polymerization degree of 130-250, a whiteness of 90-99%, S₁₀of 5-20% and S₁₀ of 1-10%.(15) The porous cellulose aggregate according to (5), in which theaforementioned natural cellulose substance is a wood pulp having alevel-off polymerization degree of 130-250, a whiteness of 90-99%, S₁₀of 5-20% and S₁₈ of 1-10%.(16) The method for producing the porous cellulose aggregate accordingto (6), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(17) The method for producing the porous cellulose aggregate accordingto (7), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(18) The method for producing the porous cellulose aggregate accordingto (8), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(19) The method for producing the porous cellulose aggregate accordingto (9), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(20) The method for producing the porous cellulose aggregate accordingto (10), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(21) The method for producing the porous cellulose aggregate accordingto (11), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(22) The method for producing the porous cellulose aggregate accordingto (12), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(23) The method for producing the porous cellulose aggregate accordingto (13), in which the aforementioned natural cellulose substance is awood pulp having a level-off polymerization degree of 130-250, awhiteness of 90-99%, S₁₀ of 5-20% and S₁₈ of 1-10%.(24) A compacting (molding) composition containing one or more groups ofactive ingredients and the porous cellulose aggregate according to anyone of (1)-(3).(25) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregateaccording to (4).(26) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregateaccording to (5).(27) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to (6).(28) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to (7).(29) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to any one of (8)-(10).(30) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to (11).(31) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to (12).(32) A compacting (molding) composition characterized by containing oneor more groups of active ingredients and the porous cellulose aggregatethat can be obtained by the method according to (13).(33) The compacting (molding) composition according to (24) that is atablet.(34) The compacting (molding) composition according to any one of(25)-(28) that is a tablet.(35) The compacting (molding) composition according to (29) that is atablet.(36) The compacting (molding) composition according to any one of(30)-(32) that is a tablet.

Advantages of the Invention

Since the porous cellulose aggregate of the present invention issuperior in compactibility, fluidity and disintegration property, inusing the porous cellulose aggregate of the present invention as anexcipient in production of a molded body containing various activeingredients, a molded body having a good homogeneous miscibility with anactive ingredient, no variation of weight, a good uniformity in activeingredient content, a sufficient hardness, no tablet press problems, lowfriability loss and a good disintegration property can be provided by asimple method.

Since the porous cellulose aggregate of the present invention greatlyenhances elution tablet pressing and disintegration property of theactive ingredient in a solid formulation containing an active ingredientwhich is hard to be soluble in water, it is especially useful as anexcipient for the solid formulation. Further, since the porous celluloseaggregate of the present invention prevents the effusion of a liquid orsemi-solid active ingredient and improves disintegration property in asolid formulation containing the liquid or semi-solid active ingredient,it is especially useful as an excipient for the solid formulation. Inaddition, in mixing of the active ingredient and components other thanthe active ingredient or in a solid formulation using thereof, when anactive ingredient exists in a minute amount, and in particular when theaverage particle size of the active ingredient is small and theattachment aggregation characteristic is high, the porous celluloseaggregate of the present invention can contribute to a mixing rate of anactive ingredient and to a reduction of the variation of concentration,and improves tablet pressing and disintegration property, and thus it isespecially useful as an excipient for the solid formulation. Stillfurther, the porous cellulose aggregate of the present invention canprevent recrystallization by a sublimation of a sublimatable activeingredient in a solid formulation of the sublimatable active ingredientand prevent a reduction of the market value, and thus it is especiallyuseful as an excipient for the solid formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the pore size distribution of the porous cellulose aggregate(Example 1) of the present invention measured by mercury porosimetry;

FIG. 2 is the pore size distribution of cellulose powder H (ComparativeExample 3) measured by mercury porosimetry;

FIG. 3 is an electron micrograph of cellulose particle K (ComparativeExample 6) at a magnification of ×250;

FIG. 4 is an electron micrograph of cellulose powder M (ComparativeExample 8) at a magnification of ×250;

FIG. 5 is an electron micrograph of cellulose particle K (ComparativeExample 6) at a magnification of ×1500. From this photo it is seen thatthe septa are film like and the boundaries of the primary particles areunclear;

FIG. 6 is a particle cross section photograph of the porous celluloseaggregate of the present invention (Example 1) by an electronmicroscope; and

FIG. 7 is a particle cross section photograph of cellulose powder M(Comparative Example 8)) by an electron microscope.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described particularly centered around thepreferred mode as follows.

The porous cellulose aggregate of the present invention must have asecondary aggregate structure composed of aggregated primary particles.This is the secondary aggregate structure having clear boundaries of theprimary particles when the surface of the particles is observed at amagnification of ×250 or ×1500 by a scanning electron microscope (SEM).The secondary aggregate structure formed by the aggregation of theprimary particles is closely related to disintegration property, and thestructure without this particular structure is not preferable becausethe disintegration property is deteriorated. When the boundaries of theprimary particles are not clear, for example having the dense andcontinuous cellulose septa, it is not preferable because the particlesdo not disintegrate in water and the disintegration property of a moldedbody becomes also poor due to the densely continued and tightly boundprimary cellulose particles.

Further, the secondary aggregate structure formed by the aggregation ofthe primary particles is also closely related to not only disintegrationproperty but also elution of an active ingredient. Water permeability tothe porous cellulose particles having the secondary aggregate structureformed by the aggregation of the primary particles is fast, anddisintegration of the primary particles are accelerated, and when anactive ingredient is retained, the elution of the active ingredientwhich is hard to be soluble in water is effectively improved because thecontact area between the active ingredient and water is increased.

In addition, this secondary aggregate structure is homogeneouslydistributed whether in the inside or on the surface of the particles,and is preferred because, when the secondary aggregate structure ismixed with an active ingredient, the active ingredient can be retainedbetween gaps of the primary cellulose particles and in particular,effusion of the liquid component can be prevented.

Still further, this secondary aggregate structure is preferred becauseit allows retention of the active ingredient not only on the surface butalso inside of the particles, and therefore it contributes to theimprovement of the mixing rate of the active ingredient and mixinguniformity, and can greatly reduce the variation of the concentration.

In the porous cellulose aggregate of the present invention theintraparticular pore volume must be 0.265 cm³/g-2.625 cm³/g. Porousparticles having a large intraparticular pore volume are superior inplastic deformability, and since the particles tend to collapse oncompression, they are superior in compactibility. The porous celluloseaggregate of the present invention is derived originally from cellulosein which the pore volume of the aggregated particles is intentionallyenlarged, and thus the plastic deformability is increased by changingthe structure of the particles themselves. For that reason the particlesexpress high compression compactibility irrespective of the apparentspecific volume of the particles. When the intraparticular pore volumeis less than 0.265 cm³/g, the primary cellulose particles have only theintraparticular pores that the primary cellulose particles originallyhave or that are formed naturally on aggregating cellulose, notintentionally formed, and thus they are poor in plastic deformability.To improve the compactibility, the apparent specific volume of theparticles must be larger, resulting in poor fluidity. The porouscellulose aggregate of the present invention can keep a goodcompactibility with a relatively small apparent specific volume, and asa result the aggregate having also a superior fluidity can be obtained.

When the intraparticular pore volume is 0.265 cm³ or larger, sufficientpore volume is present in the particles, and an active ingredient, whichis once incorporated in the pores on the surface of the particles duringthe mixing process and compression process, is not released easily, andthus these particles are preferred because sufficient amount of theliquid component can be retained in the intraparticular pores, and theeffusion can be prevented. When a solid active ingredient is used, thefinely ground active ingredient can be retained homogeneously and inlarge amount to improve water dispersion and elution, and therecrystallization of sublimatable active ingredient is prevented,especially the recrystallization during storage is prevented, and thusthese particles are preferred because they can contribute to thestabilization and prevention of degeneration of the commercial value,and further they are preferred because they can contribute to theimprovement of a mixing rate and mixing uniformity of the activeingredient and can reduce the variation of the concentration greatly.

When an active ingredient which is hard to be soluble in water is usedby dissolving temporally, suspending or emulsifying, they are preferredbecause they are superior in retaining a liquid component. A drugconcentration variation coefficient that is an index of the variation ofthe concentration of an active ingredient is preferably not over 3.0%during the mixing period, more preferably 2.0% or less, and especiallypreferably 1.5% or less. Especially when an active ingredient that hasan average particle size of 10 μm or less and has extremely highaggregatability is mixed with cellulose particles having theintraparticular pore volume of 0.265 cm³/g or higher such as the porouscellulose aggregate of the present invention, it is preferred becausethe active ingredient is retained not only on the surface of theparticles but also inside of the particles and thus the drugconcentration variable coefficient can be 2.0% or less.

When the intraparticular pore volume is less than 0.265 cm³/g, theeffect described above can not be obtained because the dispersionuniformity and retention capacity of a solid or liquid active ingredientare impaired, causing variation of the concentration of the activeingredient, aggregation of solid formulation, poor compressioncompactibility, recrystallization of sublimative active ingredientsduring storage and lowering of the stability and commercial value, andtherefore it is not preferred.

The larger the intraparticular pore volume is, the better, but the porevolume that a particle can have is limited and is at most 2.625 cm³/g.

Furthermore, if the pore volume exceeds 2.625 cm³/g, it is not preferredbecause the apparent specific volume is increased and the fluidity isdecreased.

As described above, the larger the intraparticular pore volume, the moreit is preferred because the compactibility is higher due to the particlehaving plastic deformability, the active ingredient is incorporatedinside, improving the elution, the ground active ingredient is retainedin a large quantity, recrystallization of the sublimative component canbe prevented, the mixing rate of the active ingredient is increased, themixing uniformity is improved, the liquid component can be retained andthe like, but when the intraparticular pore volume is too large, theapparent specific volume tends to be increased and the fluidity isdecreased and therefore the preferred range of the intraparticular porevolume where the compactibility and fluidity are in good balance is0.265 cm³/g-1.500 cm³/g, and especially preferred range is 0.265cm³/g-1.000 cm³/g.

The distribution of pore diameter of the porous cellulose aggregate ofthe present invention is measured, for example, by mercury porosimetry.It is preferred that a clear peak is identified especially in the rangeof 0.1-10 μm. Further, the median pore diameter that is a peak top ofthe pore distribution is closely related to water permeability into theparticle, and is preferably 0.3 μm or larger. Water permeability becomeslarger when the median pore diameter is 0.3 μm or larger, and thedisintegration property is improved further. The larger the median porediameter the more preferable, but it is at most in the range of 10-15μm.

In the production method according to Patent Document 1, two or moregroups of primary cellulose particles having different average particlesize were mixed and dried, and thus the packing among the particles wastoo good and it was difficult to obtain the pore diameter substantiallyof 3 μm or larger. The present invention is especially superior in thebalance of the compactibility and disintegration property, and thepreferred median pore diameter is 3-15 μm and more preferred is 3-10 μm.

The crystalline structure of the porous cellulose aggregate of thepresent invention must be the type I. The crystalline structure ofcellulose, type I, II, III, IV and the like are known, and among themtype I and type II are called as “natural cellulose” and “regeneratedcellulose”, respectively and are used in general, but type III and IVare obtained in laboratory scale only and not generally used inindustrial scale. Natural cellulose has been consumed as a plant fiberfoodstuff from ancient times and is widely used at present as adispersion stabilizer for liquid foodstuffs and an excipient forpharmaceutical products. On the other hand, regenerated cellulose is aproduct of the altered crystalline structure which is regenerated byremoving solvents and the cellulose solution of a chemical such ascarbon disulfide, sodium hydroxide or the like, and some of them areused as a compacting agent for foodstuffs in a wet processing. Theregenerated cellulose of type II crystalline structure is not preferred,because with altered crystalline structure from natural cellulose oftype I crystalline structure, the particles become stiff, have decreasedplastic deformability on compression and cannot give a sufficienthardness to the molded bodies.

In the porous cellulose aggregate of the present invention, the averageparticle size must be over 30 μm and 250 μm or less. When the averageparticle size is 30 μm or less, cellulose particles aggregate eachother, the active ingredient is not diffused homogeneously in mixingwith the active ingredient, the variation of the active ingredient tendsto be greater in the molded body obtained, and the variation of theweight of the molded body in the continuous production also tends to begreater. Further, when the average particle size is over 250 μm,separation and segregation tend to occur in continuous compression of apowder formulation mixed with an active ingredient having poor fluidity.

The specific surface area of the porous cellulose aggregate of thepresent invention must be 0.1 m²/g or larger and less than 20 m²/g. Atthe specific surface area less than 0.1 m²/g, the compressioncompactibility is lower, and it is difficult to give a molded body highhardness and low friability. Further, when the specific surface area isover 20 m²/g, it is not preferable to mix an active ingredient thattends to be inactivated by cellulose, because the contact area betweencellulose and the active ingredient is excessively too large, and theactive ingredient tends to lose activity.

The repose angle of the porous cellulose aggregate of the presentinvention must be 25° or larger and less than 44°. Normally, an activeingredient is prepared so that when administered, it diffuses in gastricjuice and intestinal juice media and enhances drug effect rapidly, andfor that reason it is often grounded or is fine powder from thebeginning. Since it is fine powder, the fluidity is poor, and at therepose angle of 44° or larger, it is not preferred for the fluidity ofthe mixed powder when a large amount of an active ingredient having poorfluidity is mixed. Especially, there is tendency of the variation of theweight of the molded bodies at high speed tablet pressing at a speed ofseveral ten thousands-several hundred thousands tablets/hour. Thefluidity is better with the smaller repose angle and the repose angle of25°-42° is especially good. More preferable is a repose angle of25°-40°. The repose angle of less than 25° is not preferable forseparation and segregation of the active ingredient.

The porous cellulose aggregate of the present invention must have aswelling rate of 5% or larger, preferably of 6-50%, especiallypreferably of 7-30%. The swelling degree can be measured as follows.From the volume (V₁) of about 10 g of a powder slowly poured into acylindrical container having a volume of 100 cm³, and the volume (V₂)after standing for 8 hours after adding about 50 cm³ of pure water tothe powder layer and mixing so that the powder is completely wet, usingfollowing formula the swelling degree is obtained.

Swelling degree (%)=(V₂−V₁)/V₁×100

Swelling degree is a gap between the primary cellulose particles createdwhen the primary cellulose particles are aggregated by drying, and thelarger is the value, the easier to disintegrate due to elevated waterpermeability into the particles. In the conventional cellulose powder,the one having a high compactibility has to reduce the swelling degreeresulting in sometimes insufficient disintegration property, and for theother having a high fluidity, although the swelling degree is high andthe disintegration property is good, it is difficult to have a highlevel of compactibility. Among the conventional cellulose powder, theone having the best balance for compactibility and disintegrationproperty is the porous cellulose aggregate of Patent Document 1. Thereis no description of the swelling degree in that document, but themeasurement of the porous cellulose aggregate according to Exampledescribed in that Patent Document revealed that the higher thecompactibility, the lower the value of the swelling degree, and it was4% at most. So far it has not been achieved to increase compactibilitywhile maintaining disintegration property by keeping swelling degree athigh level, and the present invention has achieved this for the firsttime.

The apparent specific volume of the porous cellulose aggregate of thepresent invention is preferably 2.0-6.0 cm³/g. The porous celluloseaggregate of the present invention has hardness, fluidity anddisintegration property in a good balance in almost whole part of theapparent specific volume compared to the conventional one because of theporous structure. To obtain a high compression compactibility, theapparent specific volume is preferably 2.0 cm³/g or larger, and toobtain a higher fluidity the apparent specific volume is preferable 6.0cm³/g or less. Especially preferred apparent specific volume is 2.5-5.0cm³/g.

For the porous cellulose aggregate of the present invention, cylindricalmolded bodies, obtained by weighing 0.5 g of the cellulose powder,placing it in a die (KIKUSUI SEISAKUSHO LTD, Material SUS2, 3 wereused), compressing with a circular flat punch with a diameter of 1.1 cm(KIKUSUI SEISAKUSHO LTD, Material SUS2, 3 were used) until the pressureof 10 MPa and 20 MPa was attained (AIKOH ENGINEERING CO., LTD. PCM-1Awas used. The compression rate was 1 cm/minute), and holding at thetarget pressure for 10 seconds, have preferably the hardness of 60 N orhigher and 165 N or higher, respectively. If the hardness of 10 MPa isless than 60 N and the hardness of 20 MPa is less than 165 N under eachcondition, the molded bodies containing a large amount of an activeingredient produced at the rate of several ten thousands-several hundredthousands tablets/hour have a low hardness, tablet pressing problem suchas friability, capping tend to occur. The tablet hardness shown here ishigher the better, but the hardness of 10 MPa and 20 MPa products are160 N and 450 N, respectively, at most.

When the aforementioned cylindrical molded body obtained by compressingto a pressure of 10 MPa has hardness of 70-160 N, or the one obtained bycompressing to 20 MPa has hardness of 170-410 N and a repose angle isover 36° and less than 44°, the porous cellulose aggregate of thepresent invention is especially superior because at a high drug contentof about 30% by weight or more, addition of a small amount of 1-30% byweight of the porous cellulose aggregate of the present invention givesphysical property required for a formulation such as sufficientcompactibility, friability, disintegration property, content uniformityand the like. When a cylindrical molded body, obtained by weighing 0.5 gof a drug having a tablet pressing problems such as sticking, cappingand the like, placing it in a die (KIKUSUI SEISAKUSHO LTD, MaterialSUS2, 3 were used), compressing with a circular flat punch with adiameter of 1.1 cm (KIKUSUI SEISAKUSHO LTD, Material SUS2, 3 were used)until the pressure of 50 MPa was attained (AIKOH ENGINEERING CO., LTD.PCM-1A was used. The compression rate was 1 cm/minute), and holding atthe target pressure for 10 seconds, have preferably the hardness of 50 Nor lower, preferably 40 N or lower, more preferably 20 N or lower, orwhen both of the characteristics are present, the porous celluloseaggregate of the present invention is especially effective. Forconventional cellulose powder, even if the tablet pressing problems suchas sticking and capping can be controlled at a high drug content ofabout 30% by weight, the fluidity was not sufficient, and the practicalapplication was not possible due to the tablet weight CV, content CV andthe like. The present invention has markedly improved the fluidity ofthe conventional cellulose powder in the usage described above, and issuperior in expressing both compactibility and fluidity at high level,despite of the fact that compactibility and fluidity have beencontradictory characteristics until now. Further, when theaforementioned cylindrical molded body obtained by compressing to 10 MPahas hardness of 60-100 N, or the one obtained by compressing to 20 MPahas hardness of 165-410 N and a repose angle is 25-36°, the porouscellulose aggregate of the present invention is especially preferredbecause the high drug content of 30% by weight or above has becomepossible for the first time in a formulation that can contain anexcipient at about 30% by weight or more. For the conventionalcellulose, lowering the repose angle causes lowering of thecompactibility, and thus even if the cellulose powder content is about30% by weight or more, in trying to increase drug content, the cellulosepowder having good fluidity shows insufficient compactibility and thecellulose powder having good compactibility shows insufficient fluidityresulting in difficulty in formulating, but the present invention hasmarkedly improved the fluidity of the conventional cellulose powder inthe usage described above, and is superior in expressing bothcompactibility and fluidity at high level, despite of the fact thatcompactibility and fluidity have been contradictory characteristicsuntil now. For the porous cellulose aggregate of the present invention,the disintegration time of the cylindrical molded body obtained underthe condition of compressing to a pressure of 20 MPa and keeping thetarget pressure for 10 seconds by the aforementioned method ispreferably for 75 seconds or shorter for the sake of disintegrationproperty. Especially preferable if it is 50 seconds or shorter. Thisdisintegration time is shorter the better. Normally, an activeingredient is prepared so that when administered, it diffuses in gastricjuice and intestinal juice media and enhances drug effect rapidly, butwhen the disintegration time of the molded body is getting longer, andthe drug is eluted from the molded body slower and not absorbed at thedigestive tract quickly, and the rapid drug effect tends to bedecreased.

Since compression compactibility and disintegration property arecontradictory characteristics and the porous cellulose aggregate of thepresent invention raised these characteristics to a level not achievedbefore, preferably the hardness of the cylindrical molded body obtainedby compressing to 10 MPa is 60-160 N, or the hardness of the cylindricalmolded body obtained by compressing to 20 MPa is 165-410 N and thedisintegration time is 75 seconds or shorter, and especially preferablythe hardness of the cylindrical molded body obtained by compressing to10 MPa is 60-160 N, or the hardness of the cylindrical molded bodyobtained by compressing to 20 MPa is 165-410 N and the disintegrationtime is 50 seconds or shorter. Since the porous cellulose aggregate ofthe present invention can be made with a larger median pore diametercompared to the porous cellulose aggregate of the Patent Document 1, ithas a higher swelling degree, and when compared at the same hardness, ithas an advantage of having a shorter disintegration time.

A formulated powder is obtained by placing 55 weight parts ofacetaminophen (API Corporation, powder type), 0.25 weight parts of lightanhydrous silicic acid (NIPPON AEROSIL CO., LTD., Commercial name:Aerosil 200), 27 weight parts of cellulose powder, 2 weight parts ofcrospovidone (BASF, Commercial name: Collidone CL) and 15 weight partsof granular lactose (Lactose New Zealand, Commercial Name: Super-Tab) ina 100 L scale V Type Mixer (Dalton Co., Ltd.) and mixing for 30 minutes,and then adding 0.5 weight parts of magnesium stearate (TAIHEI CHEMICALINDUSTRIAL CO., LTD., Plant origin) and mixing for further 5 minutes.Thus obtained formulated powder is subjected to tablet pressing using arotary tablet press (KIKUSUI SEISAKUSHO LTD, Commercial name: LIBRA-II,36 lines, Rotary table φ410 mm) and a punch with 8 mm diameter and 12 R,at a turn table speed of 50 rpm, at a compression force of 7.5 kN. Forthe porous cellulose aggregate of the present invention it is preferablethat thus obtained 200 mg molded body has a hardness of 50 N or higherand a friability of less than 1% and no tablet pressing problem.

An excipient having high compactibility is required to give hardness andto reduce friability to a formulation containing a large quantity of adrug having poor compactibility, and at the same time an excipienthaving fluidity is required to reduce the variation of weight when ahigh speed and continuous compacting is performed. Such a formulationcontaining a large amount of a drug having low compactibility and theproduction of the molded body at such a high speed can only be realizedby mixing the excipient having good compactibility and good fluiditysuch as the present invention. When the hardness of the molded body isless than 50 N and the friability is 1% or larger, it is not preferredbecause abrasion, dust generation, cracking and chipping occur duringtransportation. Occurrence of tablet pressing problems is not preferredbecause inferior products are produced. The hardness here is higher thebetter but is at most 100 N, and the friability is lower the better.

For the porous cellulose aggregate of the present invention the tablethardness of the compacting composition is preferably 50-100 N (tabletpressing pressure range: 1-10 kN) and the variation of tablet weight (CVvalue) is preferably 2.0 or less when the repose angle of the finalwhole formulated powder which composes the compacting composition of thepresent invention is 25°-45° by adding 30-90% by weight of celluloseparticles to 0.001-50% by weight of a formulated powder having poorfluidity consisting of an active ingredient and components other thancellulose particles and having a repose angle of 45°-55°, and tabletsare pressed at the high speed of 50,000 tablets or more per hour.Preferably the whole formulated powder has a repose angle of 45° orless, the tablet hardness of the compacting composition is 50-100 N andthe variation of the tablet weight (CV value) is 1.5% or less, andespecially preferably the whole formulated powder has a repose angle of42° or less, the tablet hardness of the compacting composition is 50-100N and the variation of the tablet weight (CV value) is 1.0% or less(Example 17-19 and Comparative Example 80-91).

In direct tablet pressing and the like, when the fluidity of the activeingredient in the composition and components other than the porouscellulose aggregate of the present invention is bad (repose angle of45°-55° and/or the compression compactibility of such components arepoor, it is one of the characteristics that a remarkable effect can beobtained by mixing the porous cellulose aggregate of the presentinvention in a large quantity which could not be obtained byconventional cellulose particles and cellulose powder, because theporous cellulose aggregate of the present invention has compactibility,fluidity and disintegration property in a good balance. That is, inconventional cellulose powder and cellulose particles, thecompactibility increases as the added amount of cellulose is increasedbut the fluidity and disintegration property are getting poorer due tothe fluidity being closer to that of cellulose powder and celluloseparticles themselves, and consequently there were problems that the highspeed tablet pressing at a practical production speed was difficult andthat the disintegration of thus obtained tablets was delayed. Againstsuch problems, the porous cellulose aggregate of the present inventionhas an advantage of the fluidity being improved rather than gettingworse when the porous cellulose aggregate of the present invention ismixed in a large quantity, because the porous cellulose aggregate of thepresent invention has a superior balance in the compactibility andfluidity, disintegration property at such a high level which is notattainable by the conventional cellulose powder and cellulose particles.“Mixing in a large quantity” in the present invention means that thecomposition contains 30-90% of the porous cellulose aggregate of thepresent invention. Preferably the content is 30-80% and especiallypreferably 30-70%.

Following is the description of the method for producing the cellulosepowder of the present invention.

To produce the porous cellulose aggregate of the present invention, forexample, a dispersion containing a natural cellulose material(hereinafter also designated as cellulose dispersion) needs to beobtained in which the average particle size of the primary celluloseparticles is 10 μm or larger and less than 50 μm, the average width is2-30 μm, and the average thickness is 0.5-5 μm. It is preferable becauseentanglement of the primary cellulose particles to each other can bepromoted during the drying process by making the primary celluloseparticles in such a shape. In the past, it was difficult to keep theshape of aggregated particles spherical because the longer the majoraxis of the primary cellulose particles is, the more difficult forentanglement of particles to occur. However, the present invention hasfocused on the shape of the primary cellulose particles and proven forthe first time that the entanglement of the particles can be promoted bycontrolling it in a specific range. By promoting the entanglement of theprimary cellulose particles each other, it became possible for the firsttime to make the aggregated particles in a spherical form in an easilycontrollable manner and to enhance plastic deformability of theparticles thus giving compactibility more easily by creating gaps insideof the aggregated particles. In the past, to control the shape ofaggregated particles spherical, the major axis of the primary celluloseparticles need to be shortened. However, during the process of treatingthe primary cellulose particles by a mechanical treatment or hydrolysis,or a combination of both, the shorter the major axis of the primarycellulose particles becomes, the more of the fine fragments of theprimary cellulose particles are generated, creating the problem thatthese fine fragments occupy the gap between the aggregated particles anda sufficient mold deformity can not be obtained and the compactibilityis decreased. Thus, it was necessary to granulate particles withoutshortening the major axis of the primary cellulose particles, but suchparticles are difficult to aggregate and to improve sphericity. Sincethe generation of the fine fragments of the primary cellulose particlesdescribed above in large quantity causes filling of the gaps between theaggregated particles, it is preferable to prepare a cellulose dispersionthat contains 10% by weight or less particles that are not sedimentedunder a centrifuge condition with a centrifugal force of 4900 m/s². Theporous cellulose aggregate of the present invention can be obtained bythe method for production including a step of drying that cellulosedispersion.

The natural cellulose substance in the present invention may be derivedfrom plants or animals and includes fibrous substances derived fromnatural products containing cellulose, for example, wood, bamboo, straw,cotton, ramie, bagasse, kenaf, beet, ascidian and bacterial cellulose,and may have a crystalline structure of type I cellulose. Among theabove natural cellulose substances, one group may be used as a materialor a mixture of two or more groups can be used. It is preferable to beused in the form of purified pulp but the purification of the pulp isnot particularly restricted, and any of the dissolved pulp, kraft pulp,NBKP pulp and the like may be used. The pulp derived from wood ispreferable because of the high purity of α-cellulose, easiness toobtain, the supply being stable and the like.

It is preferably a wood pulp in which a level off polymerization degreemeasured by the copper ethylenediamine solution method is 130-250, andwhiteness 90-99%, S₁₀ is 5-20% and S₁₈ is 1-10%. The level offpolymerization degree of less than 130 is not preferable because thecompactibility is hard to be expressed. The polymerization degree ofover 250 is not preferable because the average width and averagethickness of the primary cellulose particles are hard to control in aspecified range. The whiteness of less than 90 is not preferable becausethe external appearance of the porous cellulose aggregate is poor. Thewhiteness is higher the better but is at most about 99%. S₁₀ and S₁₈ ofoutside the range described above are not preferable in thecompactibility and yield. Here, in the natural cellulose substance, thematerial such as pulp may be hydrolyzed or not hydrolyzed. If hydrolyzedin particular, it may be acid hydrolysis, alkali hydrolysis, thermalhydrolysis, steam explosion or the like, and may be any one of themethod or a combination of two or more methods.

In the method described above, a medium that is used for dispersing asolid containing the natural cellulose substance is preferably water butis not particularly restricted as long as it can be used industrially,for example, a mixture of water and an organic solvent may be used. Theorganic solvent includes, for example: alcohols such as methanol,ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol andbenzyl alcohol; hydrocarbons such as pentane, hexane, heptane andcyclohexane; ketones such as acetone and ethylmethyl ketone. Inparticular, the organic solvent that can be used for pharmaceutical useis preferred and includes those classified as solvents in“Pharmaceutical additives” (published by Yakuji Nippo Limited.). Waterand organic solvents are freely used singly or in combination of two ormore, and after dispersing the cellulose in one kind of medium, themedium is removed and the cellulose may be dispersed in a differentmedium.

The porous cellulose aggregate of the present invention needs to beproduced by preparing a cellulose dispersion, in which the primarycellulose particles have an average particle size of 10 μm or above andless than 50 μm, an average width of 2-30 μm, an average thickness of0.5-5 μm, and which contains 5-40% by weight of the solid fraction, bysubjecting the natural cellulose substance to treatments that are notparticularly restricted as long as they are publicly known, for example,mechanical treatment such as milling and grinding, or chemical treatmentsuch as hydrolysis or an appropriate treatment of a combination of both,and then by drying the dispersion.

The primary cellulose particles in the present invention mean particleshaving the size in the range of 1-500 μm in which the fibers are splitand newly formed, in the case of fibers composing the natural cellulosesubstance, or in the cases where the natural cellulose substance issubjected to mechanical treatments such as milling and grinding or thenatural cellulose substance is subjected to chemical treatment such ashydrolysis. A method for making the average particle size of the primarycellulose particles less than 50 μm is achieved, for example, by amechanical treatment such as milling and grinding, or a publicly knownseparation treatment such as cyclone, centrifugation and sieving or anappropriate combination of both by controlling appropriately conditionsgenerally known to influence the treatment such as the amount to betreated, shearing force (rotating rate, shape and size of rotating wingsand the like can influence), centrifugal force and the size of the sievemesh, or for example, by a chemical treatment such as acid hydrolysis bychanging appropriately conditions such as acid concentration andtemperature, or in addition to these by changing appropriatelyconditions that are already known to influence the mechanical treatmentand separation treatment described above.

Performing hydrolysis at higher acid or alkali concentration andreaction temperature, in general, the polymerization degree of cellulosetends to be lower and the average dispersed particle size of cellulosein the dispersion tends to be smaller. Also stirring the solution withmore force, the average dispersed particle size of cellulose tends to besmaller. Therefore, by controlling the stirring force in the steps ofhydrolysis and/or dispersion of the natural cellulose substance, thepolymerization degree of the material cellulose can be controlled in thedesired range. Since the stirring force is dependent on a width, height,volume of the stirring layer, a kind of wing, a wind diameter, thestirring rotation rate and the like, it is difficult to define in aspecific range, but it is preferable that the product of the wingdiameter (m) and the stirring rotation rate (rpm) is in the range of5-200, more preferably 10-150, especially preferably 10-120.

A method for making the primary cellulose particles have an averagewidth of 2-30 μm, an average thickness 0.5-5 μm is not particularlyrestricted as long as the method, for example, splits the primarycellulose particles to a longitudinal direction, and includes a methodthat subjects wood pulp to a treatment such as a high pressurehomogenizer treatment and optionally to a mechanical treatment such asgrinding and a fraction treatment or an appropriate combination of both.In the high pressure homogenizer treatment a pressure may beappropriately controlled in the range of 10-200 MPa but it may also bedependent on the amount to be treated. Also, a pulp may be selected andused in which the primary cellulose particles have an average width of2-30 μm and an average thickness of 0.5-5 μm. The cellulose dispersionis preferably prepared containing particles that are not precipitated bya centrifugal of condition centrifugal force of 4900 m/s² at 10% byweight or less, and such methods includes, for example, in the case ofacid hydrolysis, a method for changing the hydrolysis conditionsappropriately so that the hydrolysis is difficult to proceed, a methodfor removing fine particle components that are hard to precipitate fromthe residue or the dispersion by the separation treatment or the like,or a combination of both methods.

In the hydrolysis of a natural cellulose substance there is a tendencythat the higher the acid concentration and the higher the temperature,the more fine particle components that are hard to precipitate aregenerated, but since the extent of hydrolysis is different depending onthe degree of polymerization of the natural cellulose substance, originof the material, the extraction method for the cellulose substance suchas method for producing pulp and the like, it is difficult to define thehydrolysis conditions in a universal way. However, an appropriatehydrolysis condition can be readily determined by measuring the weightof particles which are not precipitated at a centrifugal condition ofcentrifugal force of 4900 m/s² under which the % by weight of theparticles is 10% by weight or less.

The centrifugal condition of centrifugal force of 4900 m/s² in thepresent invention means to determine the rotating rate for eachcommercially available centrifuge considering the rotating radius (usingthe maximum radius) of the centrifuge using the calculation method for acentrifugal force defined by the following formula, and under thecondition of such rotating rate to perform a centrifugation at the rangeof the temperature of 15-25° C. for 10 minutes. As the commerciallyavailable centrifuge, an inverter-multi purpose high speed refrigeratedcentrifuge (Type 6930, KUBOTA Corporation, Rapid was used as a mode foracceleration and deceleration) and a RA-400 angle rotor (volume: 50 cm³,material: polypropylene co-polymer, tube angle: 35°, the maximum radius:10.5 cm, the minimum radius: 5.8 cm, rotation rate: 4100 rpm) arepreferably used.

Centrifugal force (m/s²)=11.18×(rotation rate (rpm)/1000)²×rotationradius (cm)×9.8 (m/s²)

To prepare a cellulose dispersion, in which the average particle size ofthe primary cellulose particles is 10 μm or above and less than 50 μm,an average width is 2-30 μm and an average thickness is 0.5-5 μm(preferably, in addition to these, particles that are not precipitatedat the centrifugal condition of centrifugal force of 4900 m/s² are 10%by weight or less), contributes to form gaps inside the aggregate due tothe entanglement each other between the neighboring primary celluloseparticles when aggregates of the primary cellulose particles are formed,because the primary cellulose particles having a specific average widthand average thickness are flexible when the cellulose dispersion isdried, and further preferably contributes for the gaps formed in theaggregates, without being embedded by the particles, to continue formingporous secondary aggregate structure having a large intraparticular porevolume after drying because among the primary cellulose particles in thecellulose dispersion, 10% by weight or less of the particles are notprecipitated at the centrifugal condition of centrifugal force of 4900m/s².

When the average particle size of the primary cellulose particles become50 μm or larger, the secondary aggregate structure is hard to form evenif the shape of the primary cellulose particles is in the specificrange, and the primary particles are dried individually and this is notpreferable in the aspect of the intraparticular pore volume. Further theapparent specific volume becomes too large and this is not preferable inthe aspect of the fluidity.

When the average particle size of the primary cellulose particles is 10μm or less, the inter-particular bonding force is too strong when theparticles form the secondary aggregate structure and this is notpreferable in the aspect of disintegration property. When the averagewidth of the primary cellulose particles exceeds 30 μm, the primarycellulose particles become difficult to bend, and the entanglementbetween neighboring primary cellulose particles is decreased, and thisis not preferred in the aspect of the intraparticular pore volume. Whenthe average width of the primary cellulose particles is less than 2 μm,the particles aggregate densely and the intraarticular pores are notformed. This is not preferred because the compactibility anddisintegration property are worsened. When the average thickness of theprimary cellulose particles is over 5 μm, the primary celluloseparticles become difficult to bend, and the entanglement betweenneighboring primary cellulose particles is decreased, and this is notpreferred in the aspect of the intraparticular pore volume. The lowerlimit of the average thickness of the primary cellulose particles is thelower, the easier it is for the particles to entangle, and this ispreferable in the aspect of the intraparticular pore volume, but this isat most about 0.5 μm. When the width of the primary cellulose particlesis less than 2 μm and the thickness is less than 0.5 μm, such fineparticles are bound tightly, and the intraparticular pore volume becomessmall and thus this is not preferred because of poor compactibility anddisintegration property.

The primary cellulose particles are preferably used which has a particleshape having the ratio of the average values of the major axis and minoraxis (L/D) of 2.0 or above. The larger is the L/D, the more effective itis in inhibiting excessive particle aggregate in drying, and thiscontributes to give a larger pore volume in the particles.

The cellulose dispersion of the present invention is not particularlyrestricted and may be produced by any one of the methods selected fromi) a method for producing the cellulose dispersion using the primarycellulose particles by treating one or plurality of natural cellulosesubstances, ii) a method for producing the cellulose dispersion bydividing the cellulose dispersion of the aforementioned i), treatingseparately and then mixing, iii) a method for producing the cellulosedispersion by fractionating the cellulose dispersion of theaforementioned i) or ii), treating them separately and then mixing againor iv) a method for producing the cellulose dispersion by mixing two ormore groups of the primary cellulose particles prepared separately, andfrom the economical point of view i) is especially preferable. Thetreatment method used here may be a wet method or a dry method, orrespective products obtained by the wet method may be mixed beforedrying, or respective products obtained by the dry method may be mixedbefore drying or products obtained by the wet method and dry method maybe combined. The treatment method may be a publicly known method and thelike, and not particularly restricted, including, for example, amechanical treatment such as milling and grinding, and a separationtreatment such as centrifugal separation using a cyclone or a centrifugeand sieving using a thieve. The method may be used singly or incombination of both methods.

The grinding method may be a grinding method using the stirring blade ofthe one-way rotating, multi-shaft rotary, reciprocating/reversing,vertically moving, rotating+vertically moving, or duct type such as aportable mixer, a spatial mixer, a side mixer, or the like, a jet-typestirring/grinding method such as a line mixer, a grinding method using ahigh-shear homogenizer, a high-pressure homogenizer, an ultrasonichomogenizer, or the like; or a grinding method using a rotating axisextrusion kneader. The milling method to be used may be any one of: ascreen milling method such as a screen mill and hammer mill; a rotatingblade shear screen milling method such as a flush mill; a jet millingmethod such as a jet mill; a ball milling method such as a ball mill,vibration ball milling; a screw type stirring milling method; and thelike.

The cellulose dispersion particle mixture obtained by the aforementionedprocedure is preferably made into a dispersion of a concentration of5-40% by weight before drying. If the concentration is less than 5% byweight, the average particle size of the cellulose particles to beobtained decreases and the self-fluidity tends to be impaired. Also, ifthis concentration is over 40% by weight, the apparent specific volumeof the cellulose particles becomes smaller and the compressioncompactibility tends to be impaired. The preferable concentration is10-40% by weight and the more preferable concentration is 15-40% byweight.

The drying method is not particularly restricted and any method such asfreeze drying, spray drying, drum drying, shelf drying, air streamdrying and vacuum drying may be used, and a single method or acombination of two or more methods may be used. The spray method inperforming spray drying may be any of the method selected from the discspray, pressurized nozzle, pressurized two fluid nozzle and pressurizedfour fluid nozzle, and a single method or a combination of two or moremethods may be used. From the economical point of view, the spray dryingis preferable.

On performing the aforementioned spray drying, a minute amount of awater soluble macromolecule or surfactant may be added to the dispersionto reduce the surface tension, and a foaming agent or a gas may be addedto the dispersion to accelerate the vaporization rate of the medium.

The water soluble macromolecule includes water soluble macromoleculesdescribed in “Pharmaceutical additives” (published by Yakuji NippoLimited.) such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethyleneglycol, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, gumArabic and starch glue, and one kind may be used alone or a combinationof two kinds or more may be used.

The surfactant includes surfactants classified as such in“Pharmaceutical additives” (published by Yakuji Nippo Limited.), forexample, phospholipids, glycerin fatty acid ester, polyethylene glycolfatty acid ester, sorbitan fatty acid ester, polyoxyethylene hardenedcaster oil, polyoxyethylenecetyl ether, polyoxyethylene stearyl ether,polyoxyethylenenonylphenyl ether, polyoxyethylenepolyoxypropyleneglycol, polyoxyethylenesorbitan monolaurate, polysorbate, sorbitanmonooleate, glyceride monostearate, monooxyethylenesorbitanmonoparmitate, monooxyethylenesorbitan monostearate,polyoxyethylenesorbitan monooleate, sorbitan monopalmitate, sodiumlaurylsulfate, and these are used alone or a combination of two kinds ormore may be used freely.

The foaming agent includes foaming agents described in “Pharmaceuticaladditives” (published by Yakuji Nippo Limited.), for example, tartaricacid, sodium bicarbonate, potato starch, anhydrous citric acid,medicinal soap, sodium laurylsulfate, lauric diethanolamide,macrogoallaurate, and one kind may be used alone or a combination of twokinds or more may be used. Also, other than the pharmaceuticaladditives, bicarbonate such as sodium bicarbonate and ammoniumbicarbonate that generate gas by pyrolysis, and carbonates such assodium carbonate and ammonium carbonate that generate gas by reactingwith acids may be used. However, when carbonates described above are tobe used, an acid must be used together. The acid includes: organic acidssuch as citric acid, acetic acid, ascorbic acid, adipic acid; protonicacids such as hydrochloric acid, sulfuric acid, phosphoric acid andnitric acid; Lewis acids such as boron fluoride, and the one used forpharmaceuticals/foods is preferred but others have the similar effect.In place of the foaming agent, gases such as nitrogen, carbon dioxide,liquefied petroleum gas and dimethyl ether may impregnate thedispersion.

These water soluble macromolecules, surfactants and gas generatingsubstances may be added before drying and the timing of addition is notparticularly restricted.

The compacting composition in the present invention may contain one kindor more of the active ingredients and the porous cellulose aggregate ofthe present invention, and the amount is not particularly restricted,but normal range of the usage is 0.001-99% for the active ingredient and1-99% for the cellulose powder of the present invention. Further, it canbe processed by publicly known methods such as mixing, stirring,granulating, regulating particle size and pressing tablet. When theactive ingredient is less than 0.001%, the effective dosage fortreatment cannot be obtained, and at over 99%, the porous celluloseaggregate of the present invention is less than 1% and the molded bodyhaving practical hardness, friability and disintegration property isdifficult to obtain. The compacting composition of the present inventioncan freely contain not only an active ingredient and cellulose particlesbut also optionally an excipient, disintegrator, binder, fluidizer,lubricant, tasting agent, flavoring agent, coloring agent, sweetener.

Examples of the compacting composition of the present invention forpharmaceutical use include tablets, powder, fine granules, granules,extracts and pills. The present invention includes the compactingcompositions used for not only pharmaceuticals but also foods such assweets, health foods, taste improvers, dietary fiber supplements andcosmetic solid foundations, bathing agents, veterinary drugs, diagnosticagents, agricultural chemicals, fertilizers, ceramic catalysts.

The active ingredient in the present invention means pharmaceutical drugcomponents, agricultural chemical components, fertilizer components,animal feeds components, food components, cosmetic components, dyes,flavoring agents, metals, ceramics, catalysts and surfactants, and maytake any form such as solid (powder, crystalline and the like), oil,liquid or semi solid. Also a coating may be applied to control elution,reduce bitter taste and the like. The active ingredients may be usedalone or in combination of a plurality of them. The active ingredientmay be used by dissolving, suspending or emulsifying in a medium.

For example, a pharmaceutical drug component that is administered orallysuch as an antipyretic analgesic antiphlogistic, hypnotic,antisleepiness drug, antidizziness drug, pediatric analgesic, stomachic,antacid, digestive drug, cardiotonic, antiarrhythmic drug,antihypertensive, vasodilator, diuretic, antiulcer drug, intestinalregulator, antiosteoporosis drug, antitussive expectorant, antiasthmaticdrug, antibacterial drug, anti-pollakiuria drug, analeptic and vitamincan be the active ingredient. The drug component can be used alone or incombination of two kinds or more freely.

The pharmaceutical active ingredient of the present invention includespharmaceutical drug components described in “Pharmacopeia of Japan”,“Rule for Unofficial Drugs”, “USP”, “NF”, “EP”, such as aspirin, aspirinaluminum, acetaminophen, ethenzamide, salicylosalicylic acid,salicylamide, lactyl phenetidine, isothibenzyl hydrochloride,diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterolhydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride,thonzylamine hydrochloride, fenethazine hydrochloride, methdilazinehydrochloride, diphenhydramine salicylate, carbinoxaminediphenyldisulfonate, alimemazine tartarate, diphenehydramine tannate,diphenylpyraline theoclate, mebhydrolin napadisilate,promethazinemethylene disalicylate, carbinoxamine maleate,dl-chlorpheniramine maleate, dl-chlorpheniramine maleate, difeterolphosphate, alloclamide hydrochloride, cloperastine hydrochloride,petoxyverine citrate (carbetapentane citrate), tipepidine citrate,sodium dibunate, dextromethorphan hydrobromide, dextromethorphanphenolphthalinate, tipepidine hibenzate, cloperastine fendizoate,codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride,noscapine, dl-methylephedrine hydrochloride, dl-methylephedrinesaccharin salt, guaiacol potassium sulfonate, guaifenesin, caffeinesodium benzoate, caffeine, anhydrous caffeine, vitamin B1 andderivatives and salts thereof, vitamin B2 and derivatives and saltsthereof, vitamin C and derivatives and salts thereof, hesperidine andderivatives and salts thereof, vitamin B6 and derivatives and saltsthereof, nicotinamide, calcium pantothenate, aminoacetic acid, magnesiumsilicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesiumoxide, dihydroxy aluminum aminoacetate (aluminum glycinate), aluminumhydroxide gel (as dried aluminum hydroxide gel), dried aluminumhydroxide gel, dried mixed gel of aluminum hydroxide/magnesiumcarbonate, co-precipitates of aluminum hydroxide/sodium bicarbonate,co-precipitates of aluminum hydroxide/calcium carbonate/magnesiumcarbonate, co-precipitates of magnesium hydroxide/aluminum potassiumsulfate, magnesium carbonate, magnesium aluminometa silicate, ranitidinehydrochloride, cimetidine, famotidine, naproxen, dichlophenac sodium,piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, difenidolhydrochloride, diphenylpyraline hydrochloride, diphenhydraminehydrochloride, promethazine hydrochloride, meclizine hydrochloride,dimenhydrinate, diphenhydramine tannate, phenetazine tannate,diphenylpyraline theoclate, diphenhydramine fumarate,promethazinemethylene disalicylate, spocolamine hydrobromide,oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixenehydrochloride, atropine methylbromide, anisotropine methylbromide,spocolamine methylbromide, methyl bromide-1-hyoscyamine, benactiziummethylbromide, belladonna extract, isopropamide iodide,diphenylpiperidinomethyldioxolan iodide, papaverine hydrochloride,aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate,aminophylline, diprophylline, theophylline, sodium bicarbonate,fursultiamine, isosorbide nitrate, ephedrine, cephalexin, ampicillin,sulfixazole, sucralfate, allylisopropylacetylurea, bromovalerylurea orthe like, and ephedra herb, nandia fruit, cherry bark, polygala root,glycyrrhiza, platycodon root, plantago seed, plantago herb, senega,fritillaria, fennel, phellodendron bark, coptis rhizome, zedoary, germancamomile, cinnamon bark, gentiana, oriental bezoar, animal bile,ladybells, ginger, atractylodes lancea rhizome, citrus unshiu peel,atractylodes rhizome, earthworm, panax rhizome, ginseng, kanokoso,moutan bark, zanthoxylum fruit, and extracts thereof, and insulin,vasopressin, interferon, urokinase, serratiopeptidase and somatostatin.One kind selected from the above group may be used alone or in acombination of two or more.

The active ingredient hard to be soluble in water in the presentinvention means, for example, a pharmaceutical active ingredient, onegram of which requires 30 ml or more water to dissolve according to the14^(th) edition Japanese Pharmacopeia. If it is hard to be soluble inwater, the effect can be obtained by compounding as an active ingredientto the composition of the present invention regardless of the extent ofits sublimatablity or surface polarity.

The solid active ingredient hard to be soluble in water includespharmaceutical drug components described in “Pharmacopeia of Japan”,“Rule for Unofficial Drugs”, “USP”, “NF”, “EP”, such as: antipyreticanalgesics, drugs for nervous system, sedative hypnotic drugs, musclerelaxant, antihypertensive drugs, anti-histamine drugs, such asacetaminophen, ibuprofen, benzoic acid, ethenzamide, caffeine, camphor,quinine, calcium gluconate, dimethyl caprol, sulfamin, theophylline,theopromine, riboflavin, mephenesin, phenobarbital, aminophyllin,thioacetazone, quercetin, rutin, salicylic acid, sodium theophyllinate,pyrapital, quinine HCl, irgapirin, digitoxin, griseofulvin andphenacetin; antibiotics such as acetylspiramycin, ampicillin,erythromycin, xatamycin, chloramphenicol, triacetyloleandomycin,nystatin and colistin sulfate; steroid hormones such asmethyltestesterone, methyl-androsterone-diol, progesterone, estradiolbenzoate, ethinyl estradiol, deoxycorticosterone acetate, cortisoneacetate, hydrocortisone, hydrocortisone acetate and prednisolone;non-steroid progestogen such as dienestrol, hexastrol,diethylstillbesterol, diethylstillbesterol propionate, chlorotrianisene;and other lipid soluble vitamins, and one kind selected from the abovegroup may be used alone, or a combination of two kinds or more may beused freely.

The oily or liquid active ingredient hard to be soluble in water used inthe present invention includes pharmaceutical drug components describedin “Pharmacopeia of Japan”, “Rule for Unofficial Drugs”, “USP”, “NF”,“EP”, for example: vitamins such as teprenone, indomethacin•farnesyl,menatetrenone, phytonadione, vitamin A oil, fenipentol, vitamin D andvitamin E; highly unsaturated fatty acids such as DHA (docosahexaenoicacid), EPA (Eicosapentaenoic acid) and cod liver oil; coenzyme Qs; lipidsoluble flavoring agents such as orange oil, lemon oil and peppermintoil. Vitamin E has various isomers and derivatives, but is notparticularly restricted as long as they are liquid at normaltemperature. For example, dl-α-tocopherol, dl-α-tocopherol acetate,d-α-tocopherol and d-α-tocopherol acetate are included, and one kindselected from the above group may be used alone or in a combination oftwo or more kinds may be used freely.

The semisolid active ingredient hard to be soluble in water include forexample: Chinese medicines or herbal extracts such as earthworm,glycyrrhiza, cinnamon bark, peony root, moutan bark, Japanese valerian,zanthoxylum fruit, ginter, citrus unshiu peel, ephedra herb, nandiafruit, cherry bark, polygala root, platycodon root, plantago seed,plantago herb, red spider lily, senega, fritillaria, fennel,phellodendron bark, coptis rhizome, zedoary, german camomile, gentiana,oriental bezoar, animal bile, ladybells, ginger, atractylodes lancearhizome, clove, chinhi, atractylodes rhizome, panax rhizome, ginseng,kakkonto, keishito, kososan, saikeishito, shosaikoto, shoseiryuto,bakumondoto, hangekobokuto and Maoto; oyster extract, propolis andpropolis extract and coenzyme Qs, and one kind selected from the abovegroup may be used alone or in a combination of two or more kinds may beused freely. The solid formulation composition of the present inventionmay further contain other physiologically active components in additionto the water insoluble active ingredients described above.

The finely ground active ingredient used in the present invention meansthe one finely ground to 1-40 μm or below for targeting to improve thedispersibility of the solid active ingredient hard to be soluble inwater, the mixing uniformity of an active ingredient with pharmaceuticaleffect even in a small amount and the like. The smaller is the averageparticle size, the greater is the effect of the present invention. Morepreferable average particle size of the active ingredient is 1-20 μm andstill more preferable diameter is 1-10 μm.

The sublimatable active ingredient of the present invention is notparticularly restricted as long as it is sublimatable, and may be solid,liquid or semi solid at normal temperature.

The sublimatable active ingredient includes sublimatable pharmaceuticaldrug components described in “Pharmacopeia of Japan”, “Rule forUnofficial Drugs”, “USP”, “NF”, “EP”, for example, benzoic acid,ethenzamide, caffeine, camphor, salicylic acid, phenacetin andibuprofen. One kind selected from the above group may be used alone orcombination of two or more may be used freely. The solid formulationcomposition of the present invention may further contain otherphysiologically active components in addition to the sublimative activeingredients described above.

The liquid active ingredient at normal temperature used in the presentinvention includes pharmaceutical drug components described in“Pharmacopeia of Japan”, “Rule for Unofficial Drugs”, “USP”, “NF”, “EP”,for example: vitamins such as teprenone, indomethacin•farnesyl,menatetrenone, phytonadione, vitamin A oil, fenipentol, vitamin D andvitamin E; highly unsaturated fatty acids such as DHA (docosahexaenoicacid), EPA (Eicosapentaenoic acid) and cod liver oil; coenzyme Qs; lipidsoluble flavoring agents such as orange oil, lemon oil and peppermintoil. Vitamin E has various isomers and derivatives, but is notparticularly restricted as long as they are liquid at normaltemperature. For example, dl-α-tocopherol, dl-α-tocopherol acetate,d-α-tocopherol and d-α-tocopherol acetate are included, and one kindselected from the above group may be used alone or a combination of twoor more kinds may be used freely.

The semisolid active ingredient at normal temperature used in thepresent invention include for example: Chinese medicines or herbalextracts such as earthworm, glycyrrhiza, cinnamon bark, peony root,moutan bark, Japanese valerian, zanthoxylum fruit, ginter, citrus unshiupeel, ephedra herb, nandia fruit, cherry bark, polygala root, platycodonroot, plantago seed, plantago herb, red spider lily, senega,fritillaria, fennel, phellodendron bark, coptis rhizome, zedoary, germancamomile, gentiana, oriental bezoar, animal bile, ladybells, ginger,atractylodes lancea rhizome, clove, chinhi, atractylodes rhizome, panaxrhizome, ginseng, kakkonto, keishito, kososan, saikeishito, shosaikoto,shoseiryuto, bakumondoto, hangekobokuto and Maoto; oyster extract,propolis and propolis extract and coenzyme Qs, and one kind selectedfrom the above group may be used alone or a combination of two or morekinds may be used freely.

The excipient includes excipients classified as such in “Pharmaceuticaladditives” (published by Yakuji Nippo Limited.) such as, starchacrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid,molasses (powder), gum Arabic, gum Arabic powder, alginic acid, sodiumalginate, gelatinized starch, pumice particles, inositol,ethylcellulose, ethylene-vinylacetate copolymer, sodium chloride, oliveoil, kaolin, cacao butter, casein, fructose, pumice particles,carmellose, carmellose sodium, hydrated silicone dioxide, dried yeast,dried aluminum hydroxide gel, dried sodium sulfate, dried magnesiumsulfate, agar, agar powder, xylitol, citric acid, sodium citrate,disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate,L-glutamine, clay, clay 3, clay particles, croscarmellose sodium,crospovidone, magnesium aluminosilicate, calcium silicate, magnesiumsilicate, light anhydrous silicate, light liquid paraffin, cinnamonpowder, crystalline cellulose, crystalline cellulose carmellose sodium,crystalline cellulose (particles), genmaikoji, synthetic aluminumsilicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch,wheat germ flour, rice flour, rice starch, potassium acetate, calciumacetate, cellulose acetate phthalate, safflower oil, bleached beeswax,zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin,dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol,dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, burntgypsum, sucrose fatty acid ester, magnesium-aluminum hydroxide, aluminumhydroxide gel, co-precipitates of aluminum hydroxide/sodium bicarbonate,magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calciumstearate, polyoxyl stearate, magnesium stearate, hardened soybean oil,purified gelatin, purified shelac, purified white sugar, purifiedgranule sugar, cetostearyl alcohol, polyethylene glycol 1000 mono cetylether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalciumphosphate, soybean oil, unsaponified soybean product, soybean lecithin,defatted powdered milk, talc, ammonium carbonate, calcium carbonate,magnesium carbonate, neutral anhydrous sodium sulfate, low substitutionhydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate,corn starch, tragacanth powder, silicon dioxide, calcium lactate,lactose, granular lactose, Perfiller 101, white shellac, white vaseline,white clay, white sugar, white sugar/starch granule, powder of greenleaf extract of rye, dried powder of green juice of bud leaf of rye,honey, paraffin, potato starch, half digested starch, human serumalbumin, hydroxypropylstarch, hydroxypropylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose phthalate, phytic acid, glucose, glucosehydrate, partially gelatinized starch, pullulan, propylene glycol,reduced maltose molasses powder, powdered cellulose, pectin, bentonite,sodium polyacrylate, polyoxyethylenealkyl ether, polyoxyethylenehardened caster oil, polyoxyethylene (105) polyoxypropylene (5) glycol,polyoxyethylene (160) polyoxypropylene (30) glycol, sodiumpolystyrenesulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, polyethyleneglycol, maltitol, maltose,D-mannitol, molasses, isopropyl myristate, anhydrous lactose, anhydrouscalcium hydrogen phosphate, granular anhydrous calcium hydrogenphosphate, magnesium aluminometa silicate, methylcellulose, cotton seedpowder, cotton seed oil, wood wax, aluminum monostearate, glycerinmonostearate, sorbitan monostearate, medical charcoal, peanut oil,aluminum sulfate, calcium sulfate, granular corn starch, liquidparaffin, dl-malic acid, calcium monohydrogen phosphate, calciumhydrogen phosphate, granular calcium hydrogen phosphate, sodium hydrogenphosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphateand sodium dihydrogen phosphate, and one kind selected from the abovegroup may be used alone or a combination of two or more kinds may beused freely.

The disintegrator includes integrators classified as such in“Pharmaceutical additives” (published by Yakuji Nippo Limited.) forexample: celluloses such as, croscarmellose sodium, carmellose,carmellose calcium, carmellose sodium and low substitutionhydroxypropylcellulose; starches such as carboxymethylstarch sodium,hydroxypropylstarch, rice starch, wheat starch, corn starch, potatostarch and partially gelatinized starch; and synthetic polymers such ascrospovidone and crospovidone co-polymer. One kind selected from theabove group may be used alone or a combination of two or more kinds maybe used freely.

The binder includes binders classified as such in “Pharmaceuticaladditives” (published by Yakuji Nippo Limited.) for example: sugars suchas white sugar, glucose, lactose and fructose; sugar alcohols such asmannitol, xylitol, maltitol, erythritol and sorbitol; water solublepolysaccharides such as gelatin, pullulan, carrageenan, locust bean gum,agar, glucomannan, xanthan gum, tamarindo gum, pectin, sodium alginateand gum Arabic; celluloses such as crystalline cellulose, powderedcellulose, hydroxypropylcellulose and methylcellulose; starches such asgelatinized starch and starch glue; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer and polyvinyl alcohol; and inorganiccompounds such as calcium hydrogen phosphate, calcium carbonate,synthetic hydrotalcite and magnesium aluminosilicate. One kind selectedfrom the above group may be used alone or a combination of two or morekinds may be used freely.

The fluidizing agent includes fluidizing agents classified as such in“Pharmaceutical additives” (published by Yakuji Nippo Limited.) forexample silicon compounds such as hydrated silicon dioxide and lightanhydrous silicate. One kind selected from the above group may be usedalone or a combination of two or more kinds may be used freely.

The lubricant includes lubricants classified as such in “Pharmaceuticaladditives” (published by Yakuji Nippo Limited.) for example magnesiumstearate, calcium stearate, stearic acid, sucrose fatty acid ester andtalc. One kind selected from the above group may be used alone or acombination of two or more kinds may be used freely.

The tasting agent includes tasting agents classified as such in“Pharmaceutical additives” (published by Yakuji Nippo Limited.) forexample glutamic acid, fumaric acid, succinic acid, citric acid, sodiumcitrate, tartaric acid, malic acid, ascorbic acid, sodium chloride and1-menthol. One kind selected from the above group may be used alone or acombination of two or more kinds may be used freely.

The flavoring agent includes flavoring agents classified as such in“Pharmaceutical additives” (published by Yakuji Nippo Limited.) forexample oils such as orange, vanilla, strawberry, yogurt, menthol,fennel oil, cinnamon oil, picea oil and peppermint oil, green teapowder. One kind selected from the above group may be used alone or acombination of two or more kinds may be used freely.

The dye includes dyes classified as such in “Pharmaceutical additives”(published by Yakuji Nippo Limited.), for example, food dyes such asfood dye red No. 3, Food dye yellow No. 5, food dye blue No. 1, copperchlorophyn sodium, titanium oxide and riboflavin. One kind selected fromthe above group may be used alone or a combination of two or more kindsmay be used freely.

The sweetener includes sweeteners classified as such in “Pharmaceuticaladditives” (published by Yakuji Nippo Limited.) for example aspartame,saccharin, dipotassium glycyrrhizinate, stebia, maltose, maltitol,morasses and powder of Hydrangea macrophylla var. thunbergii. One kindselected from the above group may be used alone or a combination of twoor more kinds may be used freely.

Following is the description of the method for production of thetablets, the main components of which are one or plurality of activeingredients and the porous cellulose aggregates of the presentinvention, but this is an example and the effect of the invention is notlimited by the following method. The method can be used including a stepof mixing an active ingredient and the porous cellulose aggregates ofthe present invention and then a step of compression compacting. Duringthese steps additives other than the active ingredient can be mixedoptionally, and one or more kind of the components for example selectedfrom the group shown above such as excipients, disintegrators, binders,fluidizers, lubricants, tasting agents, flavors, dyes, sweeteners andsolubilizers may be added.

The order of the addition of the respective components is notparticularly restricted, and any of the method may be used, i) by whichthe active ingredient, the porous cellulose aggregates of the presentinvention and optionally other additives are mixed altogether andsubjected to compression compacting or ii) by which the activeingredient, and the additives such as the fluidizer and/or lubricant arepre-mixed and then mixed with the porous cellulose aggregates of thepresent invention and, optionally, with other additives, andsubsequently the mixture is subjected to compression compacting. Thelubricant may be added to the powder mixture for compression compactingobtained in i) or ii), mixing is continued and then the mixture may besubjected to compression compacting.

When an active ingredient hard to be soluble in water is especiallyused, the following production method can be used. The productionmethods, for example, may be any of, the methods: i) by which the activeingredient is ground or used as it is, mixed with the porous celluloseaggregates of the present invention and optionally with the otheradditives, and then the mixture is subjected to compression compacting,or ii) by which, after dissolving or dispersing the active ingredient inwater and/or an organic solvent and/or a solubilizer, the solution ordispersion is absorbed to the porous cellulose aggregate of the presentinvention and/or optionally to the other additives, and mixed with theporous cellulose aggregate and/or optionally with the other additives,and after distilling off water and/or the organic solvent optionally,the mixture is subjected to compression compacting.

Among i), in particular, it is preferable from the view point ofcompactibility and fluidity that after mixing an active ingredient withadditives such as a fluidizer in advance, the active ingredient is mixedwith the porous cellulose aggregates of the present invention andoptionally with other components and subjected to compressioncompacting. The crystalline form of the active ingredient beforecompression compacting may be the same or different from that before theformulation, it is preferable to be the same from the view point of thestability. When using a water insoluble active ingredient, it iseffective to use a water soluble polymer or surfactant in combinationespecially as a solubilizer to disperse the active ingredient into themedium. Here, the other additive means an additive other than the porouscellulose aggregates of the present invention, including, for example,the aforementioned excipients, disintegrators, binders, fluidizers,lubricants, tasting agents, flavors, sweeteners and solubilizers. Theseadditives may be used alone or in a combination of two or more kinds.

In the cases of ii) in particular, since the active ingredient that ishard to be soluble or insoluble in water goes through a step ofsolubilization or dispersion once, an improving effect for the elutionof the active ingredient can be expected. When a liquid dispersionmedium such as polyethylene glycol is used in combination as adispersion medium for a pharmaceutical active ingredient, the dispersedbecomes liquid or semi-solid even if the active ingredient is originallya crystalline powder, and thus tablet formulation therefrom isimpossible unless a substance such as the porous cellulose aggregate ofthe present invention having superior compression compactibility andfluidity is used. Further, when polyethylene glycol or the like is usedas a dispersing agent for a pharmaceutical active ingredient, it is saidthat the active ingredient absorbed in the body takes a structurecovered by polyethylene glycol in the blood stream, and thus it isexpected that the effect of the active ingredient that is easilymetabolized in the liver lasts longer.

A method for adding each component is not particularly restricted if itis commonly practiced method, and either the continuous addition or onetime addition may be performed using a small suction transport device,air transport device, bucket conveyer, pressure transport device, vacuumconveyer, quantitative vibration feeder, spray, funnel and the like.

When the active ingredient is a solution, suspension or emulsion, it ispreferable to adopt a method of spraying that to the porous celluloseaggregates of the present invention or to the other additive because itreduces the variation of the concentration of the active ingredient inthe final products. The spray method may be any methods for spraying thesolution/dispersion of the active ingredient using a pressure nozzle,2-fluid nozzle, 4-fluid nozzle, rotating disc, ultrasonic nozzle or thelike, or methods for instilling the solution/dispersion of the activeingredient from a tube like nozzle. When the solution/dispersion of theactive ingredient is added, the active ingredient may be layered on thesurface of the porous cellulose aggregate particles by layering orcoating treatment, may be held inside of the porous cellulose aggregateparticles, or the solution/dispersion of the active ingredient may beused as a binding agent for granulating the porous cellulose aggregateparticles or a mixture of the porous cellulose and the other additivesin a matrix-like structure. The layering and coating treatment may beperformed by a wet method or a dry method.

A method for mixing is not particularly restricted if it is a commonlypracticed method, and it may use a vessel rotation type mixer such as aV type, W type, double corn type, or container tack type mixer, astirring mixer such as a high-speed agitation type, universal agitationtype, ribbon type, pug type, or nautor type mixer, a super mixer, a drumtype mixer, or a fluidized bed type mixer. In addition, a vessel shakingtype mixer such as a shaker may be also used.

A method for the compression compacting of the composition is notparticularly restricted if it is a commonly practiced method; a methodwhich includes using a die and a punch for making the composition into adesired form by means of the compression compacting or a method whichincludes preliminarily making the composition into sheet form by meansof the compression compacting, and cutting into a desired form may beused. A compression compacting machine may use, for example, a rollertype press such as a hydrostatic press, a briquetting roller type press,or a smoothing roller type press, or a compressor such as a single-punchtableting machine or a rotary tableting machine.

A method for dissolving or dispersing an active ingredient in a mediumis not particularly restricted if it is carried out by the usualdissolution or dispersion method; a stirring/mixing method such as aportable mixer, a spatial mixer, a side mixer, or the like using thestirring blade of the one-way rotating, multi-shaft rotary,reciprocating/reversing, vertically moving, rotating+vertically moving,or duct type, a jet-type stirring/mixing method such as a line mixer, agas-blowing stirring/mixing method, a mixing method using a high-shearhomogenizer, a high-pressure homogenizer, an ultrasonic homogenizer, orthe like, or a mixing method of vessel shaking type using a shaker, orthe like may be used.

A solvent used in the production method described above is notparticularly restricted if it is used for pharmaceuticals and includessolvents classified as such in “Pharmaceutical additives” (published byYakuji Nippo Limited.), for example, alcohols such as methanol, ethanol,isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzylalcohol, hydrocarbons such as pentane, hexane, heptane and cyclohexane,ketones such as acetone and ethylmethylketone, and one kind selectedfrom the above group may be used alone or a combination of two or morekinds may be used freely, or after dispersing with one kind of solvent,the solvent may be removed and another solvent may be used fordispersion.

A water soluble polymer as a solubilizer includes water soluble polymersdescribed in “Pharmaceutical additives” (published by Yakuji NippoLimited.), for example, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyacrylic acid, carboxyvinylpolymer,polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone,methylcellulose, ethylcellulose, gum Arabic and starch glue, and thesemay be used alone or in a combination of two or more freely.

Fat and oils as a solubilizer include fat and oils described in“Pharmaceutical additives” (published by Yakuji Nippo Limited.), forexample, monoglyceride stearate, triglyceride stearate, sucrose stearateester, paraffins such as liquid paraffin, carnauba wax, hardened oilssuch as hardened castor oil, castor oil, stearic acid, stearyl alcoholand polyethyleneglycol; these may be used alone or in a combination oftwo or more kinds freely.

A surfactant as a solubilizer may be, for example, those classified as asurfactant in “Pharmaceutical additives” (published by Yakuji NippoLimited.), including phospholipid, glycerin fatty acid ester,polyethylene glycol fatty acid ester, sorbitan fatty acid ester,polyoxyethylene hardened castor oil, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether,polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitanmonolaurate, polysorbate, sorbitan monooleate, glyceride monostearate,monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitanmonostearate, polyoxyethylene sorbitan monooleate, sorbitanmonopalmitate, and sodium lauryl sulfate; these may be used alone or ina combination of two or more kinds.

As used herein, “tablet” refers to a molded body obtained by compressioncompacting that includes the porous cellulose aggregates of the presentinvention, one or more active ingredients, and optionally otheradditives. A composition for a tablet, formulated with the porouscellulose aggregates of the present invention has practical hardnessobtained by a simple and easy method such as direct tablet pressingwithout going through a complex process; however, any preparation methodincluding a dry granule compression method, a wet granule compressionmethod, wet granulation compression (extragranular addition ofmicrocrystalline cellulose), or a method for preparing a multicoretablet using, as inner core, a tablet preliminarily subjected tocompression compacting a method for preparing a multi-layer tablet bystacking molded bodies preliminarily subjected to compression compactingand compressing them again may be also used.

Since the porous cellulose aggregates of the present invention issuperior in various physical properties required for an excipient suchas compression compactibility, self fluidity and disintegrationproperty, it is effectively used for: tablets containing many kinds anda large quantity of drugs, which tend to cause tablet pressing troublessuch as lowering of tablet hardness, fractures on the surface of thetablet, chipping, peeling off from inside and cracking, for example, thetablets for over-the-counter drugs and tablets containing extract powdersuch as Chinese herb medicine; small tablets; non-cylinder type oddshaped tablets having a part where compression pressure is difficult tobe applied homogeneously such as a constricted edge; tablets containingdrugs like enzymes/proteins that are easily inactivated by tablettingpressure or friction with the excipient; and tablets containing coatedgranules. In addition, since the cellulose powder of the presentinvention is superior in compression compactibility and disintegrationproperty, tablets having a practical friability can be obtained at arelatively low compression pressure. For that reason, gaps (wateringcapillary) can be maintained in the tablet, it is effectively used fortablets that disintegrate quickly in the oral cavity.

Further, for multi-layer and multi-core tablets in which severalcomponents of the composition are compression molded in one ormulti-steps, the porous cellulose aggregates of the present invention iseffective, in addition to preventing the general tablet pressingtroubles described above, in preventing peeling between the layers andcracks. Having a secondary aggregate structure that is formed by theaggregation of the primary particles, the porous cellulose aggregates ofthe present invention has a good cleavability of the particle itself,and when used in a scored tablet, it is easy to cleave the tabletevenly. Still further, having a well developed porous structure, theporous cellulose aggregates of the present invention has a goodretention of drugs in a fine particulate condition, in a suspensionliquid and in solubilized solution, and thus the tablets utilizing thesehave also a good retention of drugs in a fine particulate condition, ina suspension liquid and in solubilized solution. Therefore it iseffectively used for preventing the peeling off and strengthening oflayering the coating layer and sugar coat layer of layering and coatingtablets which are treated with components in suspended liquid orsolution, and also sugar coated tablets on which components such assugar and calcium carbonate are layered.

Next, the usage of a composition containing one kind or more of theactive ingredients and the porous cellulose aggregate particles will bedescribed. The compositions that are obtained by the method describedabove containing solid, liquid and semisolid active ingredients and theporous cellulose aggregate particles may be used as a solid formulationin powder or granular conditions, or as coated powder or granular solidformulation by treating the powder or granular composition with acoating agent. The powder or granular composition with or withoutcoating may be used by filling in a capsule or may be used as a tablettype solid formulation by treating by the compression compactingprocedure. Still further capsules or tablets may be used after coating.

Here, a coating agent for applying a coating includes coating agentsdescribed in “Pharmaceutical additives” (published by Yakuji NippoLimited.), for example, a dispersion of ethyl acrylate/methylmethacrylate copolymer, acetyl glycerin fatty acid ester, aminoalkylmethacrylate copolymer, gum Arabic powder, ethylcellulose, aqueousdispersion of ethylcellulose, octyl-decyl triglyceride, olive oil,kaolin, coca butter, kagoso, castor wax, caramel, carnauba wax,carboxyvinyl polymer, carboxymethylethylcellulose, carboxymethylstarchsodium, calcium carmellose, sodium carmellose, hydrated silicon dioxide,dried aluminum hydroxide gel, dried milky white lac, dried methacrylatecopolymer, Kanbai powder (rice granules), fish scale powder, gold foil,silver foil, triethyl citrate, glycerin, glycerin fatty acid ester,magnesium silicate, light anhydrous silicic acid, light anhydroussilicic acid containing hydroxypropylcellulose, light liquid paraffin,whale wax, crystalline cellulose, hardened oil, synthetic aluminumsilicate, synthetic wax, high glucose molasses, hard wax, succinylatedgelatin, wheat flour, wheat starch, rice starch, cellulose acetate,vinyl acetate resin, cellulose acetate phthalate, bleached beeswax,titanium oxide, magnesium oxide,dimethylaminoethylmethacrylate/methylmetharylate copolymer,dimethylpolysiloxane, dimethylpolysiloxane/silicon dioxide mixture,silicon oxide mixture, burnt gypsum, sucrose fatty acid ester, jinkopowder, aluminum hydroxide gel, hydrogenated rosin glycerin ester,stearyl alcohol, stearic acid, aluminum stearate, calcium stearate,polyoxyl stearate, magnesium stearate, purified gelatin, purifiedshellac, purified white sugar, zeine, sorbitan sesquioleate, cetanol,gypsum, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol,D-sorbitol solution, tricalcium phosphate, talc, calcium carbonate,magnesium carbonate, simple syrup, burnt silver foil, precipitatedcalcium carbonate, low substituted hydroxypropylcellulose, turpentineresin, starch (soluble), corn syrup, corn oil, triacetin, calciumlactate, white shellac, white sugar, honey, hard fat, paraffin, pearlpowder, potato starch, hydroxypropylcellulose, hydroxypropylcellulose,hydroxypropylcellulose acetate succinate,hydroxypropylcellulose/titanium oxide/polyethylene glycol mixture,hydroxypropylmethylcellulose phthalate, piperonyl butoxide, castor oil,diethyl phthalate, dibutyl phthalate, butylphthalylbutyl glycolate,glucose, partially gelatinized starch, fumaric acid/stearicacid/polyvinyl acetal diethylamino acetate/hydroxypropylcellulosemixture, pullulan, propylene glycose, powder sugar, bentonite, povidone,polyoxyethylene, hardened caster oil, polyoxyethylene (105)polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30)glycol, polyoxyethylenesorbitan monostearate, polyvinyl acetaldiethylaminoacetate, polyvinyl alcohol (partially saponified),polyethylene glycol, terminal hydroxyl group substitutedmethylpolysiloxan silicone resin copolymer, D-mannitol, molasses,beeswax, myristyl alcohol, anhydrous silicic acid hydrate, anhydrousphthalic acid, anhydrous calcium hydrogen phosphate, methacrylatecopolymer, magnesium aluminometa silicate, methylcellulose,2-methyl-5-vinylpyridinemethylacrylate/methacrylic acid copolymer, woodwax, glycerin monostearate, sorbitan monostearate, sorbitanmonolaurylate, montanic acid ester wax, medical charcoal, lauromacrogol,calcium sulfate, liquid coumarone resin, liquid paraffin, dl-malic acid,calcium monohydrogen phosphate, calcium hydrogen phosphate, sodiumhydrogen phosphate, calcium dihydrogen phosphate and rosin and these maybe used alone or a combination of two kinds or more may be used freely.

Since the porous cellulose aggregates of the present invention have awell developed porous structure, and the particle itself has a superiorretention capability, the particles that retain a drug in the pores maybe used as it is as fine particles, as granules after granulation, orthese may be compression molded. These fine particles, granules andtablets may be further coated thereon. The method of retention is notparticularly restricted if it is a publicly known method, and mayinclude i) a method which includes mixing with a drug in a fine particlecondition and retaining in the pores, ii) a method which includes mixingthe porous cellulose aggregates with a drug in a powder condition undera high shearing and forcefully retaining them in the pores, iii) amethod which includes mixing the porous cellulose aggregates with a drugpreliminary dissolved or dispersed, retaining them in the pores and thenoptionally drying for retention, iv) a method which includes mixing theporous cellulose aggregates with a sublimatable drug, and sublimatingand absorbing in the pores by heating and/or reducing pressure, v) amethod include mixing and fusing the porous cellulose aggregates with adrug before or during heating and retaining fused materials in thepores, and any of the above methods may be used alone or a combinationof two kinds or more may be used.

Since the porous cellulose aggregates of the present invention have awell developed porous structure and have a suitable water holdingcapacity and oil holding capacity, they can be used not only as anexcipient but also as an core particle for layering and coating, and inthis usage they have an effect for preventing aggregation among theparticles during the process of layering and coating. The layering andcoating may be a dry method or a wet method.

Further, when an active ingredient is a solution, suspension oremulsion, a method like a dipping method, which uses the porouscellulose aggregate particles or a mixture of the porous celluloseaggregate particles and other additives as a carrier, may be used whichincludes immersing in the solution, suspension or emulsion of the activeingredient and retaining the active ingredient. Although it depends onthe conditions such as the kind of the active ingredient and theconcentration, even in the liquid immersion method such as the dippingmethod, the uniformity of the active ingredient can be maintained and itis superior compared to the spray method described above from the viewpoint of the simplicity of the process.

Still further, when the active ingredient is in a solution, suspensionor emulsion, a method may be adopted in which the porous celluloseaggregate particles or a mixture of the porous cellulose aggregateparticles and the other additives is immersed as a carrier in thesolution, suspension or emulsion of the active ingredient, and then thedispersion is spray dried to make a complex.

In the porous cellulose aggregate particles or a mixture of the porouscellulose aggregate particles and the other additives before or afterthe addition of an active ingredient solution/dispersion, the respectiveunit particles may be dispersed individually or may take a form ofaggregated granules.

When the production process includes granulation, the method forgranulation includes a dry granulation, wet granulation, heatinggranulation, spray granulation and microcapsulation. More specifically,among the wet granulation methods, fluidized bed granulation, stirringgranulation, extrusion granulation, disintegration granulation andtumbling granulation are effective. In the fluidized bed granulationmethod, the granulation is performed in a fluidized bed granulationdevice by spraying the binder solution to fluidized powder. In thestirring granulation method, mixing, kneading and granulation of thepowder are performed in a closed structure at the same time by rotatinga stirring blade in a mixing trough while the binding solution is added.In the extrusion granulation, granulation is performed by forcefullyextruding a wet lump that is kneaded by adding a binder solution througha screen of a suitable size by means of the screw method or basketmethod. In disintegration granulation, granulation is performed byshearing and disintegrating a wet lump that is kneaded by adding abinder solution by a rotating blade of a granulator, and spring granulesout of a surrounding screen by centrifugal force. In tumblinggranulation, spherical granules are tumbled by centrifugal force of arotating rotor, and at the same time a binder solution is sprayed from aspray gun to grow the particles having a homogeneous particle size likesnow balls.

Any of the methods for drying granules such as a hot air heating type(shelf drying, vacuum drying and fluidized bed drying), conduction heattype (flat pan type, shelf box type, drum type) or freeze drying typemay be used. In the hot air heating type, a material is directly incontact with hot air, and at the same time evaporated water is removed.In the conduction heat type, the material is heated indirectly through aconduction wall. In freeze drying type, the material is frozen at −10 to−40° C. and then water is removed by sublimation by heating under a highvacuum (1.3×10⁻⁵−2.6×10⁻⁴ MPa).

The methods for compression compacting include, i) a method in which amixture of an active ingredient and the porous cellulose aggregateparticles, or a mixture of one or more groups of active ingredients andthe porous cellulose aggregate particles, and optionally other additivesis compression molded by a normal method (direct tablet pressingmethod), ii) a method in which after mixing an active ingredient and theporous cellulose aggregate particles, and optionally other additives,the mixture was granulated and the granules are compression molded by anormal method (wet/dry type granule compression method), or iii) amethod in which an active ingredient and porous cellulose aggregateparticles, and optionally other additives are mixed, granulated andfurther the porous cellulose aggregate particles, and optionally otheradditives are added and compression molded by a normal method(compression compacting after wet/dry type granulation).

A method for adding one or more of active ingredients, the porouscellulose aggregates, other additives or granules is not particularlyrestricted if it is commonly practiced method, and either the continuousaddition or one time addition may be performed using a small suctiontransport device, air transport device, bucket conveyer, pressuretransport device, vacuum conveyer, quantitative vibration feeder, spray,funnel and the like.

Other than using as tablets after compression compacting, thecomposition for tablets of the present invention may be used as agranular formulation or powder formulation to improve especially thefluidity, anti-blocking and anti-coagulation characteristics because thecomposition for tablet of the present invention is superior in retentionof solid and liquid components. Any of the methods for producinggranular formulation and powder formulation, for example, a drygranulation, wet granulation, heat granulation, spray drying andmicrocapsulation may be used.

EXAMPLES

The present invention will be described based on Examples. However, theembodiment of the present invention is not limited by this descriptionof Examples. In addition, the methods for measurement and evaluation ofeach physical property in Examples and Comparative Examples are asfollows.

(1) Average Width (μm) of Primary Cellulose Particles

Primary cellulose particles consisting of a natural cellulose substancewas optionally dried, placed on a sample platform covered with a carbontape, vacuum coated with platinum/palladium (thickness of vapordeposited film is 20 nm or less), and observed using JSM-5510V(Commercial Name) made by JASCO Corporation, at an acceleration voltageof 6 kV at a magnification of ×250. The average of three representativeprimary cellulose particles was calculated.

(2) Average Thickness (μm) of Primary Cellulose Particles

Primary cellulose particles consisting of a natural cellulose substancewas optionally dried, placed on a sample platform covered with a carbontape, vacuum coated with gold, and then a cross section of a primarycellulose particle was excised by Ga ion beam using a converging ionbeam manufacturing apparatus (Hitachi, Ltd. FB-2100 (Commercial Name))and observed at an acceleration voltage of 6 kV at a magnification of×1500. The average of three representative primary cellulose particleswas calculated.

(3) Amount (% by Weight) of Particles that are not Precipitated UnderCentrifugal Condition of Centrifugal Force of 4900 m/s²

A cellulose dispersion before drying was accurately weighed (A(g)) in acentrifuge tube (50 ml capacity) and adjusted to about 1% celluloseconcentration by adding pure water. The cellulose dispersion beforedrying was weighed so that the weight after the adjustment was about 30g. The centrifuge tube containing the cellulose dispersion of about 1%concentration was placed in an inverter-multi purpose high speedrefrigerated centrifuge (Type 6930, KUBOTA Corporation, Rapid was usedas a mode for acceleration and deceleration) and a RA-400 angle rotor(volume: 50 cm³, material: polypropylene co-polymer, tube angle: 35°,the maximum radius: 10.5 cm, the minimum radius: 5.8 cm, rotation rate:4100 rpm) and centrifuged at a centrifugal force of 4900 m/s², in thetemperature range of 15-25° C. for 10 minutes. After the centrifugation,the supernatant was transferred to a weighing vial, dried at 110° C. for5 hours, and the weight of the solid cellulose after drying was measured(B(g)). In addition, the cellulose dispersion was weighed separately inthe range of 2-5 g, dried at 110° C. for 5 hours and the weight of thesolid after drying was measured (C(%)).

The amount of particles that are not precipitated under centrifugalcondition of centrifugal force of 4900 m/s², D (% by weight), wascalculated from the following formula.

D (% by weight)=(B(g)/[A(g)×(C(%)/100)])×100

(4) Average Particle Size (μm) of Cellulose Dispersion

The average particle size was expressed as a cumulative volume 50%particle by measuring the cellulose dispersed in water using a laserdiffraction particle size distribution analyzer (HORIBA, LA-910(Commercial Name)) after ultrasonic treatment of one minute, atrefractive index of 1.20. However, this measurement does not necessarilycorrelate to the particle size distribution of dried particles obtainedby the Ro-tap method described below because of entirely differentprinciple of measurement. The average particle size measured by thelaser diffraction is obtained from the volume frequency that isdependent on the major axis of the fibrous particle, while the averageparticle size obtained by the Ro-tap method is dependent on the minoraxis of the fibrous particle because the fractionation is performed byshaking the obtained powder on a sieve. Therefore, the laser diffractionmethod that depends on the major axis of the fibrous particle sometimesproduces larger figures than that of the Ro-tap method that depends onthe minor axis of the fibrous particle.

(5) Crystalline Form

An X ray diffraction analysis was conducted by an X ray diffract meterand the crystalline form was determined from the X ray pattern.

(6) Average Particle Size (μm) of Dried Particles.

The average particle size of powder sample was measured using a Ro-tapsieve shake (Taira Kosakusho Ltd., Sieve Shaker A type (CommercialName)), and JIS standard sieve (Z8801-1987) by sieving 10 g of thesample for 10 minutes and expressed as the accumulated weight 50%particle size.

(7) Specific Surface Area (m²/g)

The measurement was made by the BET method using a TriSTAR (MicrometricsCo., Commercial Name) and nitrogen as an absorbing gas. About one gramof each sample was placed in a cell and measured. Each sample powderused for the measurement had been dried at 110° C. for 3 hours underreduced pressure.

(8) Intraparticular Pore Volume (cm³/g) and Median Pore Diameter (μm)

Pore size distribution was obtained by the mercury porosimetry using anautopore type 9520 (Commercial Name, made by Shimadzu Corporation). Eachsample powder used for the measurement had been dried at roomtemperature for 15 hours under reduced pressure. From the pore sizedistribution obtained by the measurement at the initial pressure of 20kPa, “the clear peak area” in the range of pore diameter of 0.1-15 μmwas calculated as the intraparticular pore volume. Further the peak topof “the clear peak” observed in the range of pore diameter of 0.1-15 μmwas regarded as the median pore diameter from the obtained pore sizedistribution and the value was recorded.

(9) Apparent Specific Volume (cm³/g)

The powder sample was poured into a 100 cm³ measuring cylinder using aquantitative feeder or the like in 2-3 minutes and the top layer of thepowder sample was made flat using a soft brush and the volume was read.The apparent specific volume was obtained by dividing this volume withthe weight of the powder sample. The weight of the powder sample wassuitably set so that the volume was 70-100 cm³.

(10) Observation of the Particle Surface and Pores by SEM

Each cellulose sample was placed on a sample platform covered with acarbon tape and vacuum coated with platinum/palladium (thickness ofvapor deposited film is 20 nm or less), and observed using JSM-5510V(Commercial Name) made by JASCO Corporation, at an acceleration voltageof 6 kV at a magnification of ×250-×1500. A sample was regarded ◯ whenit has a secondary aggregated particle structure consisting ofcontinuously aggregated primary particles, in which the boundary betweenthe primary particles were clear and the confirmable median porediameter was 0.1 μm or above. A sample having a structure other thanthat was regarded X.

(11) Disintegration of Cellulose Particles in Water

Each cellulose sample of 0.1 g was placed in a glass test tube, mixedwith 10 g of pure water and treated with ultrasonic for 1 minute.Observations were made using a microscope (Made by Keyence Corporation,VH-7000 (Commercial name)) with or with our ultrasonic treatment, andthe presence or absence of particle disintegration was monitored. Thesample in which disintegration was observed was ◯ and not observed wasX.

(12) Reactivity to a Drug

Aspirin (Japanese Pharmacopeia crystalline aspirin was treated with asmall grinder 0.5 mm, with 1 pass treatment) and each cellulose samplewas mixed at 5/5 (total 0.5 g) in dry conditions and then placed in aglass sample vial and mixed. The vial was stored in an oven (Made byTabai Espec Corp. Perfect Oven (Commercial Name)) with the cap tightlyclosed (at 60° C.) for two weeks and then the decomposition rate wasmeasured. Ferric (III) sodium sulfate 12 hydrate 8 g was placed in a 100ml measuring flask, mixed with pure water to bring the volume up to 100ml to make a coloring test solution. 0.25 g of stored aspirin (total 0.5g of the blended powder) was introduced to a 50 ml measuring flask,mixed with ethanol to bring the volume up to 50 ml and the mixture wasshaken for 5 minutes. Thus obtained ethanol solution was filtered, thefiltrate was transferred to a 100 ml measuring flask and ethanol wasadded to bring the volume up to 100 ml. One milliliter of this ethanolsolution and 1 ml of the coloring test solution described above wereintroduced to a 50 ml measuring flask, mixed with pure water to bringthe volume up to 50 ml and the absorption was measured at the wavelengthof 532 nm using a UV absorption meter (made by JASCO Corporation). Thedecomposition rate was calculated from the following formula.

Decomposition rate (%)=(1−(absorption after the storage/absorptionbefore the storage))×100

The sample showing a decomposition rate over 15%, which is thedecomposition rate of aspirin alone was judged to be reactive.

(13) Repose Angle (°)

Using a Sugihara type repose angle measuring device (slit size: depth 10mm×width 50 mm×height 140 mm, a protractor was placed at the position of50 mm width), the dynamic self-fluidity was measured when cellulosepowder was dropped to the slit at 3 g/minute using a quantitativefeeder. The angle between the bottom of the device and the top layer ofthe cellulose powder is the repose angle.

(14) Swelling Degree

The swelling degree was obtained from the volume (V₁) of about 10 g ofpowder which was slowly poured into a cylindrical container having 100cm³ capacity and the volume (V₂) of the same powder when about 50 cm³ ofpure water was added to the powder and the result is mixed so that thepowder was thoroughly wetted and then left standing for 8 hours, by thefollowing formula.

Swelling degree (%)=(V₂-V₁)/V₁×100

(14) Compression Compacting of a Cellulose Sample Alone

0.5 g of each cellulose powder was weighed, placed in a die (KIKUSUISEISAKUSHO LTD, Material SUS2, 3 were used), compressed with a circularflat punch with a diameter of 1.1 cm (KIKUSUI SEISAKUSHO LTD, MaterialSUS2, 3 were used) until the pressure of 10 MPa and 20 MPa was attained(AIKOH ENGINEERING CO., LTD. PCM-1A was used. The compression rate was 1cm/minute), and held at the target pressure for 10 seconds, and then acylindrical molded body was taken out.

(15) Rotary Tablet Pressing of the Formulated Powder

55 weight parts of acetaminophen (API Corporation, powder type), 0.25weight parts of light anhydrous silicic acid (Nippon NIPPON AEROSIL CO.,LTD., Commercial name: Aerosil 200), 27 weight parts of celluloseparticles of powder obtained in Examples and Comparative Examples, twoweight parts of crospovidone (BASF, Commercial name: Collidone CL) and15 weight parts of granular lactose (Lactose New Zealand, CommercialName: Super-Tab) were placed in a 100 L scale V Type Mixer (Dalton Co.,Ltd.) and mixed for 30 minutes, and then 0.5 weight parts of magnesiumstearate (TAIHEI CHEMICAL INDUSTRIAL CO., LTD., Plant origin) was addedand mixed for further 5 minutes to obtain the formulated powder. Herethe total amount of input powders was 25 kg. Thus obtained formulatedpowder was subjected to tablet pressing using a rotary tablet press(KIKUSUI SEISAKUSHO LTD, Commercial name: LIBRA-II, 36 lines, Rotarytable 010 mm) and the formulated powder was supplied by a stirringfeeder. Tablet pressing was performed using a punch with 8 mm diameterand 12 R, at a turn table speed of 50 rpm, at a compression force of 7.5kN to obtain tablets weighing 200 mg each.

(16) Variation of Tablet Mass (%)

Twenty tablets obtained by the rotary tablet pressing were weighed, andthe average weight and the standard deviation of the weight werecalculated, and the variation of the mass was evaluated from thevariation coefficient defined by the formula (standard deviation/averageweight)×100. The smaller is the variation coefficient, the smaller isthe variation.

(17) Tablet Hardness (N)

Using a Schleuniger hardness tester (Freund Corporation 6D type(Commercial Name)), a cylindrical molded body or a tablet was subjectedto a load from the direction of the diameter until destroyed and theload at this time was measured. The hardness was expressed as an averageof 10 samples.

(18) Disintegration Time (Second)

The disintegration test was conducted according to the tabletdisintegration test method, in the general test method of the 14^(th)edition of the Japanese Pharmacopeia. For a cylindrical molded body or atablet the disintegration time was obtained in pure water at 37° C.using a disintegration tester (Toyama Sangyo Co., Ltd., NT-40HS type(Commercial Name), in the case of cellulose alone: with disc; in thecase of the formulation: without disc). The disintegration time wasexpressed as the average of 6 samples.

(19) Tablet Friability (% by Weight)

Twenty tablets were weighed (Wa), placed in a friability tester (JapanMachinery Company, PTF-3RA type (Commercial Name)), rotated at 25 rpmfor 4 minutes, and then fine powder attached to the tablets was removed.The weight (Wb) of the tablets was measured again and the friability wascalculated from the following formula.

Friability=100×(Wa-Wb)/Wa

(20) Incidence of Tablet Pressing Problems (%)

One hundred tablets obtained by a rotary tablet press were randomlyselected and subjected to visual inspection. The number of tablets withsplitting (lamination), breaking off (chipping) and peeling off(capping) was counted, and the total number of these tablets was dividedby the number of the inspected tablets to obtain the %.

(21) Level-Off Polymerization Degree of Wood Pulp

Ten grams of wood pulp was shredded, hydrolyzed under the condition of2.5 N hydrochloric acid, at a boiling temperature for 15 minutes andthen purified. The dried powder thus obtained was subjected tomeasurement according to the viscosity method (copper ethylenediaminemethod) described in the crystalline cellulose confirmation test (13) ofthe 13^(th) edition of the Japanese Pharmacopeia to obtain thepolymerization degree.

(22) Whiteness of Wood Pulp

This value is measured according to ISO (filter R457). The measurementwas made by a color difference meter using a blue filter regarding theperfect white as 100%. The degree of whiteness was defined as areflection rate at a transmission central wavelength of 457 μm.

(22) S₁₀, S₁₈ of Wood Pulp

A value measured according to Tappi T253m-60. S₁₀:

100 cm³ of 10% NaOH was placed in a glass container, cooled to 20° C.for 30 minutes, and 1.6 g of shredded pulp (dry weight is G) was addedand immersed well in alkali. The mixture was then stirred at 2300-2800rpm to dissolve the pulp completely. After cooling the glass containerwith water, 10 cm³ of 0.4 N potassium dichromate and 30 cm³ ofconcentrated sulfuric acid were added to 10 cm³ of the filteredsolution, and then 100 cm³ of pure water was added and the mixturecooled in water for 30 minutes. After adding 10 cm³ of 10% KI andstanding, the mixture was titrated with 0.1 N sodium thiosulfate. Thevolume of sodium thiosulfate at the endpoint was A (cm³). For 10 cm³ of10% NaOH before adding pulp, the titration described above wasperformed. The volume of sodium thiosulfate at the endpoint was B (cm³).S₁₀ is calculated from the following formula.

S₁₀(%)=(B-A)×0.685/G

G=weight of pulp×(100-water content of pulp)/100

The water content of pulp is calculated by drying the pulp at 125° C.for 1.5 hours.

S₁₈:

Was measured according to the same method as S₁₀ except that 18% NaOHwas used.

Example 1

Two kg of shredded commercially available pulp (natural cellulosedissolved pulp derived from wood, average polymerization degree: 1030,average fiber width of the primary cellulose particles: about 39 μm,average thickness: about 8 μm) was immersed in water and, under thecondition of containing about 70% water, passed through a cutter mill(URSCHEL LABORATORIES, INC. “Comitrol” (Commercial Name), Model 1700,Microhead/blade gap: 2.029 mm, Immpeler rotation rate: 9000 rpm) andmixed with pure water to prepare a cellulose dispersion of about 2%concentration, which was treated twice with a high pressure homogenizer(MFIC Corp. Commercial Name “Microfluidizer” M-140K type, Processpressure: 200 MPa) and then centrifuged at a centrifugal force of 19600m/s² to obtain the precipitates after discarding the supernatant. Theprecipitates were dried at 40° C. for 16 hours, and about 2 kg of thedried precipitates and 30 L of 4 N hydrochloric acid solution wereplaced in a low speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGLReactor (Commercial Name)). Hydrolysis was performed at 40° C. for 48hours while stirring to obtain an acid insoluble residue. Aftersufficient washing with pure water, the acid insoluble residue thusobtained was filtered, introduced to a 90 L polyethylene bucket, mixedwith pure water to bring the concentration of the total solid fractionto 20% by weight and neutralized with ammonia water while stirring witha 3-1 motor (pH after neutralization was 7.5-8.0). The average fiberwidth of the primary cellulose particles in this cellulose dispersioncontaining 20% by weight of the solid fraction was about 19 μm, averagethickness was about 3 μm and average particle size was 38 μm. Thiscellulose dispersion was spray dried (dispersion supply rate: 6 kg/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.) to obtainthe cellulose particle A that is the cellulose aggregate. The physicalproperties of the cellulose particle A are shown in Table 1.

FIG. 1 shows the results of the measurement of the pore sizedistribution of the cellulose particle A by the mercury porosimetry, andFIG. 6 shows an electron micrograph of the cross section of thecellulose particle A. As shown in FIG. 1, in the cellulose particle A, a“clear peak” that was derived from the intraparticular pores wasconfirmed in the range of 0.1-15 μm. This is about the same size as thepore size shown in the electron micrograph by SEM. In addition, the peakshown in the range of 10-50 μm in FIG. 1 is derived from the gap betweenparticles. As shown in FIG. 6, the development of the intraparticularpores having the pore diameter that corresponded to the “clear peak”shown in FIG. 1 was also observed.

Example 2

By subjecting broadleaf trees to a known pulping treatment and bleachingtreatment, a pulp was obtained having an average fiber width of theprimary cellulose particle of about 19 μm, average thickness of about 3μm, level off polymerization degree of 140-220, water content of 5-10%,whiteness of 92-97%, viscosity of 5-40 cps, S₁₀ 5-15%, S₁₈ 1-8%, coppervalue of 0.5-1.5 and dichloromethane extracts of 0.03 ppm or less. Twokilograms of this pulp and 30 L of 4 N hydrochloric acid solution wereplaced in a low speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGLReactor (Commercial Name)). Hydrolysis was performed at 40° C. for 48hours while stirring to obtain an acid insoluble residue. Aftersufficient washing with pure water, the acid insoluble residue thusobtained was filtered, introduced to a 90 L polyethylene bucket, mixedwith pure water to bring the concentration of the total solid fractionto 15% by weight and neutralized with ammonia water while stirring witha 3-1 motor (pH after neutralization was 7.5-8.0). The average fiberwidth of the primary cellulose particles in this cellulose dispersioncontaining 15% by weight of the solid fraction was about 22 μm, averagethickness was about 2.5 μm and average particle size was 38 μm. Thiscellulose dispersion was spray dried (dispersion supply rate: 6 kg/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.) to obtainthe cellulose particle B that is the cellulose aggregate. The physicalproperties of the cellulose particle B are shown in Table 1.

Example 3

By subjecting broadleaf trees to a known pulping treatment and bleachingtreatment, a pulp was obtained having an average fiber width of theprimary cellulose particle of about 19 μm, average thickness of about 3μm, level off polymerization degree of 140-220, water content of 5-10%,whiteness of 92-97%, viscosity of 5-40 cps, S₁₀ 5-15%, S₁₈ 1-8%, coppervalue of 0.5-1.5 and dichloromethane extracts of 0.03 ppm or less. Twokilograms of this pulp and 30 L of 5 N hydrochloric acid solution wereplaced in a low speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGLReactor (Commercial Name)). Hydrolysis was performed at 40° C. for 20hours while stirring to obtain an acid insoluble residue. Aftersufficient washing with pure water, the acid insoluble residue thusobtained was filtered, introduced to a 90 L polyethylene bucket, mixedwith pure water to bring the concentration of the total solid fractionto 15% by weight and neutralized with ammonia water while stirring witha 3-1 motor (pH after neutralization was 7.5-8.0). The average fiberwidth of the primary cellulose particles in this cellulose dispersioncontaining 18% by weight of the solid fraction was about 22 μm, averagethickness was about 2.5 μm and average particle size was 35 μm. Thiscellulose dispersion was spray dried (dispersion supply rate: 6 kg/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.) to obtainthe cellulose particle C that is the cellulose aggregate. The physicalproperties of the cellulose particle C are shown in Table 1.

Example 4

Two kilograms of shredded commercially available pulp (natural cellulosedissolved pulp derived from wood, average polymerization degree: 1030,average fiber width of the primary cellulose particles: about 39 μm,average thickness: about 8 μm) was immersed in water and, under thecondition of containing about 70% water, passed through a cutter mill(URSCHEL LABORATORIES, INC. “Comitrol” (Commercial Name), Model 1700,Microcuthead/blade gap: 2.029 mm, Immpeler rotation rate: 9000 rpm) andmixed with pure water to prepare a cellulose dispersion of about 2%concentration, which was treated 4 times with a high pressurehomogenizer (MFIC Corp. Commercial Name “Microfluidizer” M-140K type,Process pressure: 200 MPa) and then centrifuged at a centrifugal forceof 19600 m/s² to obtain the precipitates after discarding thesupernatant. The precipitates were dried at 40° C. for 16 hours, andabout 2 kg of the dried precipitates and 30 L of 5 N hydrochloric acidsolution were placed in a low speed stirrer (Ikebukuro Horo Kogyo Co.,Ltd., 50LGL Reactor (Commercial Name)). Hydrolysis was performed at 40°C. for 20 hours while stirring to obtain an acid insoluble residue.After sufficient washing with pure water, the acid insoluble residuethus obtained was filtered, introduced to a 90 L polyethylene bucket,mixed with pure water to bring the concentration of the total solidfraction to 20% by weight and neutralized with ammonia water whilestirring with a 3-1 motor (pH after neutralization was 7.5-8.0). Theaverage fiber width of the primary cellulose particles in this cellulosedispersion containing 20% by weight of the solid fraction was about 15μm, average thickness was about 1.5 μm and average particle size was 31μm. This cellulose dispersion was spray dried (dispersion supply rate: 6kg/hr, inlet temperature: 180-220° C., outlet temperature: 50-70° C.) toobtain the cellulose particle D that is the cellulose aggregate. Thephysical properties of the cellulose particle D are shown in Table 1.

Example 5

Two kilograms of shredded commercially available pulp (natural cellulosedissolved pulp derived from wood, average polymerization degree: 1030,average fiber width of the primary cellulose particles: about 39 μm,average thickness: about 8 μm) was immersed in water and, under thecondition of containing about 70% water, passed through a cutter mill(URSCHEL LABORATORIES, INC. “Comitrol” (Commercial Name), Model 1700,Microcuthead/blade gap: 2.029 mm, Immpeler rotation rate: 9000 rpm) andmixed with pure water to prepare a cellulose dispersion of about 2%concentration, which was treated 6 times with a high pressurehomogenizer (MFIC Corp. Commercial Name “Microfluidizer” M-140K type,Process pressure: 200 MPa) and then centrifuged at a centrifugal forceof 19600 m/s² to obtain the precipitates after discarding thesupernatant. The precipitates were dried at 40° C. for 16 hours, andabout 2 kg of the dried precipitates and 30 L of 4 N hydrochloric acidsolution were placed in a low speed stirrer (Ikebukuro Horo Kogyo Co.,Ltd., 50LGL Reactor (Commercial Name)). Hydrolysis was performed at 40°C. for 48 hours while stirring to obtain an acid insoluble residue.After sufficient washing with pure water, the acid insoluble residuethus obtained was filtered, introduced to a 90 L polyethylene bucket,mixed with pure water to bring the concentration of the total solidfraction to 15% by weight and neutralized with ammonia water whilestirring with a 3-1 motor (pH after neutralization was 7.5-8.0). Theaverage fiber width of the primary cellulose particles in this cellulosedispersion containing 15% by weight of the solid fraction was about 8μm, average thickness was about 0.6 μm and average particle size was 18μm. This cellulose dispersion was spray dried (dispersion supply rate: 6kg/hr, inlet temperature: 180-220° C., outlet temperature: 50-70° C.) toobtain the cellulose particle E that is the cellulose aggregate. Thephysical properties of the cellulose particle E are shown in Table 1.

Comparative Example 1

Two kilograms of shredded commercially available pulp (natural cellulosedissolved pulp derived from wood, average polymerization degree: 1030,average fiber width of the primary cellulose particles: about 39 μm,average thickness: about 8 μm) and 30 L of 0.14 N hydrochloric acidsolution were placed in a low speed stirrer (Ikebukuro Horo Kogyo Co.,Ltd., 50LGL Reactor (Commercial Name)). Hydrolysis was performed at 121°C. for 1 hour while stirring to obtain an acid insoluble residue. Aftersufficient washing with pure water, the acid insoluble residue thusobtained was filtered, introduced to a 90 L polyethylene bucket, mixedwith pure water to bring the concentration of the total solid fractionto 17% by weight and neutralized with ammonia water while stirring witha 3-1 motor (pH after neutralization was 7.5-8.0). The average fiberwidth of the primary cellulose particles in this cellulose dispersioncontaining 17% by weight of the solid fraction was about 39 μm, averagethickness was about 8 μm and average particle size was 36 μm. Thiscellulose dispersion was spray dried (dispersion supply rate: 6 kg/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.) to obtainthe cellulose aggregates. These cellulose aggregates were milled using ajet mill (SEISHIN ENTERPRISE CO., LTD., Single Track Jet Mill STJ-200(Commercial Name)) to obtain cellulose powder F (corresponding toExample 1 of Patent Document 6). The physical properties of thecellulose particle F thus obtained are shown in Table 1.

Results of the SEM observation of cellulose powder B indicated that theparticles did not have intraparticular pores, the primary particlesexisted alone without having the secondary aggregate structure and thatno disintegration of the particles in water was observed.

Comparative Example 2

The similar operations were performed as Comparative Example 1 exceptthat the hydrolysis condition was 3N hydrochloric acid solution, at 40°C., for 40 hours and drying at the concentration of the solid 8% toobtain cellulose powder G (corresponding to Example 5 of Patent document9). The physical properties of the cellulose powder G thus obtained areshown in Table 1. The average fiber width of the primary celluloseparticles in the cellulose dispersion before drying was 39 μm, theaverage thickness was 8 μm and the average particle size was 47 μm.

Comparative Example 3

The similar operations were performed as Comparative Example 1 exceptthat the hydrolysis condition was 3 N hydrochloric acid solution, at 40°C., for 20 hours and drying at the concentration of the solid fractionof 6% to obtain cellulose powder H (corresponding to Example 7 of PatentDocument 9). The physical properties of the cellulose powder H thusobtained are shown in Table 1. The average fiber width of the primarycellulose particles in the cellulose dispersion before drying was 39 μm,the average thickness was 8 μm and the average particle size was 49 μm.

Further, FIG. 2 shows a pore size distribution pattern of the cellulosepowder H measured by the mercury porosimtry. For the cellulose powder Hno “clear peak” like the one seen in the porous cellulose aggregates ofExample 1 was confirmed. Such pores having no “clear peak” are intrinsicto the original primary cellulose particles. Still further, consideringthe distribution of the particle size of the powder, the peak seen inthe range of 10-50 μm was derived from the gap between particles.

Comparative Example 4

The similar operations were performed as

Comparative Example 1 except that the hydrolysis condition was 4 Nhydrochloric acid solution, at 40° C., for 48 hours and drying at theconcentration of the solid fraction of 16% to obtain cellulose powder I(corresponding to Example 4 of Patent Document 9). The physicalproperties of the cellulose powder I thus obtained are shown in Table 1.The average fiber width of the primary cellulose particles in thecellulose dispersion before drying was 39 μm, the average thickness was8 μm and the average particle size was 44 μm.

Comparative Example 5

FMC Co., Ltd., product “Abicel” PH-200 was assigned to be the cellulosepowder J. The physical properties of the cellulose powder J are shown inTable 1.

Comparative Example 6

The cellulose aggregates obtained in Comparative Example 1 andacetaminophen, Japanese Pharmacopeia (MERCK HOEI CO., LTD.) milled usinga bantam mill (Made by Hosokawa Tekkosho, screen size: 2 mm) wereintroduced to a high speed stirring granulator (made by GOKYO SEISAKUSHOCO., LTD., NSK250 (Commercial Name)) in a composition of cellulose 50%by weight and acetaminophen 50% by weight, total 500 g of the powdermixture, mixed well by rotating a stirring blade at 500 rpm for 1minute, further mixed for 2 minutes while adding 245-255 g of 50% byweight ethanol solution to obtain spherical granules. The granules thusobtained were dried at 50° C. for 12 hours, and then after 12 mesh orlarger fractions were discarded as coarse large particles, acetaminophenwas extracted with acetone for 20 hours using a Soxhlet extractionapparatus. This was again dried at 50° C. for 12 hours to obtain thecellulose powder K (corresponding to Example 2 of Patent Document 2).The physical properties of the cellulose powder K thus obtained areshown in Table 1.

FIG. 3 shows an electron micrograph of the cellulose particle K at amagnification of ×250 and FIG. 5 shows an electron micrograph at amagnification of ×1500.

In the cellulose powder K, a “clear peak” was confirmed in the range of0.1-10 μm of the pore size distribution from the results of themeasurement of the pore size distribution by the mercury porosimetry.However, the electron microgram (FIGS. 3 and 5) by SEM confirmed thatthe particle structure was not the “secondary aggregate structure of theaggregation of the primary particles” but the “dense homogeneouslycontinuous film like septum structure”. From FIGS. 3 and 5, it is seenthat the primary cellulose particles became microfine particles whichbound tightly each other in drying process forming the “densehomogeneously continuous film like septum structure” resulting in thatboundaries between the primary particles became unclear. In addition,the particles did not disintegrate in water. Furthermore, thecylindrical molded body (compression pressure 10 MPa) obtained from thecellulose particle K was very much fragile and friable.

Comparative Example 7

A commercially available dissolved pulp was shredded and hydrolyzed in7% hydrochloric acid solution at 105° C. for 20 minutes, and a wet cakewas obtained by neutralizing, washing, filtering and dehydrating thusobtained acid insoluble residue. The wet cake (water content: 50% byweight) was dispersed in isopropyl alcohol and subjected to two cyclesof filtration, dehydration and re-dispersion, and further subjected tothe dispersion treatment three times using a Manton-Goring homogenizer(made by NIHONSEIKI KAISHA LTD. Type 15M (Commercial Name)) at atreatment pressure of 400 kg/cm² to obtain a cellulose dispersion havingthe solid fraction concentration of 9.8% by weight, water content of 2.5weigh %, isopropyl alcohol of 87.7% by weight. The average particle sizeof the primary cellulose particles of the cellulose dispersion havingthe solid fraction concentration of 9.8% by weight was 1 μm. Thiscellulose dispersion was spray dried using a nitrogen circulating typespray dryer. The sample thus obtained was sieved through a JIS standardsieve to cut off the coarse fraction of 250 μm or above to obtain thecellulose powder L (corresponding to Example 2 of Patent Document 3).The physical properties of the cellulose powder L thus obtained areshown in Table 1.

In the cellulose particle L, a “clear peak” was confirmed at 0.1 μm orbelow from the results of the measurement of the pore size distributionby the mercury porosimetry. Also, the electron microgram by SEMconfirmed that the particle structure was not the “secondary aggregatestructure of the aggregation of the primary particles” but the “densehomogeneously continuous film like septum structure”. The boundariesbetween the primary particles were unclear in the septa. The particlesdid not disintegrate in water, and the aspirin decomposition rate washigher than that of the drug alone.

Comparative Example 8

Two kilograms of shredded commercially available pulp (natural cellulosedissolved pulp derived from wood, average polymerization degree: 1030,average fiber width of the primary cellulose particles: about 39 μm,average thickness: about 8 μm) and 30 L of 0.14 N hydrochloric acidsolution were placed in a low speed stirrer (Ikebukuro Horo Kogyo Co.,Ltd., 50LGL Reactor (Commercial Name)). Hydrolysis was performed at 121°C. for 1 hour while stirring to obtain an acid insoluble residue. Aftersufficient washing with pure water, the acid insoluble residue thusobtained was filtered, introduced to a 90 L polyethylene bucket, mixedwith pure water to bring the concentration of the total solid fractionto 17% by weight and neutralized with ammonia water while stirring witha 3-1 motor (pH after neutralization was 7.5-8.0). The average fiberwidth of the primary cellulose particles in this cellulose dispersioncontaining 17% by weight of the solid fraction was about 39 μm, averagethickness was about 8 μm and average particle size was 36 μm. Thiscellulose dispersion was spray dried (dispersion supply rate: 6 kg/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.) to obtainthe cellulose powder M (corresponding to Example of Patent Document 4).

The physical properties of the cellulose powder M are shown in Table 1.Also an electron micrograph of the cellulose powder M at a magnification×250 is shown in FIG. 4.

From FIG. 4, it is seen that the particle structure of the cellulosepowder M is the “secondary aggregate structure of the aggregation of theprimary particles”. However, since this is the product of drying thedispersion of the cellulose particles having a single average particlesize, the intracellular pore volume is small, and no clear peak wasobserved in the range of 0.1-10 μm in the pore size distribution fromthe results of the measurement of the pore size distribution by themercury porosimetry.

Further, FIG. 7 is a cross section view of the particle of the cellulosepowder M by an electron microscope, and a tightly bound structure can beconfirmed that was formed by the stiff binding of the celluloseparticles. The intraparticular pores were sparse and not well developedand the pore volume measured by the mercury porosimetry is also small.

Comparative Example 9

Two kilograms of a commercially available kraft pulp was shredded andhydrolyzed in 0.7% by weight hydrochloric acid aqueous solution at 125°C. for 150 minutes, and the acid insoluble residue thus obtained wasfiltered and neutralized. The wet flock thus obtained was sufficientlypulverized in a kneader, mixed with an equal volume of ethanol, pressedand filtered and air dried.

The average fiber width of the primary cellulose particle in cellulosewater/ethanol dispersion before drying was 31 μm, the average thicknesswas 8 μm and average particle size was 28 μm. After air drying, it wasmilled by a normal hammer mill, and the coarse fraction was removed bysieving through a 40 mesh sieve to obtain the cellulose powder N(corresponding to Example 1 of Patent Document 5). The various physicalproperties of the cellulose powder N thus obtained are shown in Table 1.

Comparative Example 10

A commercially available dissolved pulp was shredded and hydrolized in10% by weight hydrochloric acid aqueous solution at 105° C. for 30minutes. The obtained acid insoluble residue was filtered, washed, andneutralized to obtain a dispersion with a solid fraction concentrationof 17% by weight. The primary cellulose particles in the cellulosedispersion had an average fiber width of 39 μm, an average thickness of8 μm, and an average particle size of 33 μm. The obtained cellulosedispersion was dried with a drum drier (product name KDD-1 from KusunokiKikai Seisakusho Co., Ltd. at a steam pressure of 0.35 MPa, a drumtemperature of 136° C., a drum speed of 2 rpm, and reservoir dispersiontemperature of 100° C.). This was then crushed with a hammer mill andbulk particles were removed with a sieve having a mesh size of 425 μm,providing a Cellulose Powder O (corresponds to Example 1 in PatentDocument 7). Various properties of the obtained Cellulose Powder O areshown in Table 1.

Comparative Example 11

An airjet sieve was used on the Cellulose Powder K obtained fromComparative Example 10 and large particles were removed with a 75 μmsieve and fine particles were removed with a 38 μm sieve. This providedthe Cellulose Powder P (corresponds to the Example of Patent Document8). Various physical properties of the obtained Cellulose Powder P areshown in Table 1.

Comparative Example 12

A high-speed stirrer and granulator (model FS-10 (Commercial Name) fromFukae Industries Co., Ltd.) was used with 1.5 kg of Cellulose Powder Mobtained from Comparative Example 8 and 1.5 kg of distilled water wasadded. Kneading was performed for 5 minutes. The Marumerizer Q-230(Commercial Name, Fuji Paudal Co., Ltd.) was used on 1.0 kg of the wetpowder to form spheres by rolling for 10 minutes at 500 rpm. At the sametime, 200 g of distilled water was added at a rate of 20 g/min. Then,the powder was left out overnight at 40° C. to dry, after which a 16mesh (1 mm mesh size) was used to obtain spherical particles Q(corresponds to Example 1 of Patent Document 12). The various physicalproperties of the obtained spherical particles are shown in Table 1.

The cellulose spherical particles Q are extremely heavy and providesuperior fluidity, but there was almost no specific surface area orintraparticular pore volume. A molded body could not be formed understandard compression pressures of 10, MPa.

Comparative Example 13

As in Example 1, a commercially available kraft pulp was shredded andhydrolized in a 10% by weight of hydrochloric acid aqueous solution at105° C. for 30 minutes. The obtained acid insoluble residue was filteredto obtain a crystal cellulose cake with a solid concentration of 40%(the degree of polymerization of the cake was 153). The cake was groundfor 1 hour with an all-purpose mixer/stirrer (model number 5DM-03-R(Commercial Name) from San-Ei Seisakusho, Ltd.). Water was added to theground cake and a homogenizing mixer (model number TK Homomixer Mark IIfrom Tokushu kika Kogyo) was used to form a 12.5% by weight of solidcontent cellulose dispersion with adjustments made for particle size,pH, and IC. The primary cellulose particles in the resulting cellulosedispersion had an average particle size of 7 μm. The dispersion wasspray dried using a turntable of approximately 8 cm at a rotation speedof 5000 rpm, a flow rate of 6 L/hr, an intake temperature of 170° C.,and an outlet temperature of 85° C. Large particles were removed with asieve having a mesh size of 177 μm to obtain a cellulose powder R. Thevarious physical properties of the obtained cellulose particle R(corresponds to Example 1 of Patent Document 14) are shown in Table 1.

The cellulose particles R are also heavy and have superior fluidity butspecific surface area and intraparticular pore volume are low. While amolded body could be formed under standard compression pressures of 10,20 MPa, the molded body was fragile, with friability taking place uponrelease. The molded body could be easily destroyed by hand.

Comparative Example 14

A low-speed stirrer (30LGL reactor from Ikebukuro Horo Kogyo Co., Ltd.,approximately 30 cm blade diameter) was used with 2 kg of shreddedcommercially available pulp (with a degree of polymerization of 790) and30 L of 4 N aqueous hydrochloric acid. Hydrolization was performed for48 hours at 40° C. while stirring at a stirring speed of 5 rpm,resulting in acid insoluble residue with an average polymerizationdegree of 270. The obtained acid insoluble residue was filtered to asolid concentration of 40% using a suction funnel. The filtered residuewas then washed with pure water and neutralized with ammonia water. Thiswas placed in a 90 L polyethylene bucket. Pure water was added and theresult was stirred at a stirring speed of 5 rpm using a 3-1 motor (type1200G from Heidon, 8 M/M, average blade diameter 5 cm). This provided acellulose dispersion with a solid concentration of 22%. The primarycellulose particles in the cellulose dispersion had an average fiberwidth of 39 μm, an average thickness of 8 μm, and an average particlesize of 54 μm. This was spray dried (dispersion supply rate: 6 L/hr,inlet temperature: 180-220° C., outlet temperature: 50-70° C.),resulting in a cellulose powder S. The various physical properties ofthe obtained cellulose particles S (corresponds to Example 2 of PatentDocument 10) are shown in Table 1. While the cellulose particles Sprovided a high degree of hardness in the molded body at 10, 20 MPa, theapparent specific volume was too high, resulting in inferior fluidity(repose angle) and disintegration property.

Comparative Example 15

A low-speed stirrer (30LGL reactor (Commercial Name) from Ikebukuro HoroKogyo Co., Ltd.) was used with 2 kg of shredded commercial by availablepulp (a natural cellulose dissolved pulp derived from wood) and 30 L of4 N aqueous hydrochloric acid. Hydrolization was performed for 48 hoursat 40° C. while stirring, resulting in acid insoluble residue. Afterthoroughly washing the obtained acid insoluble residue in pure water,the residue was filtered, resulting in a wet flock (the average particlesize of the dispersed cellulose particles in the acid insoluble residuewas 55 μm.) Of the obtained wet flock, 60% by weight was further washedthoroughly with pure water, neutralized, refiltered, and air dried toproduce a dried flock. This dried flock was shredded with a home mixerand then further crushed with a jet mill (single-track jet mill STJ-200from SEISHIN ENTERPRISE CO., LTD.) to obtain a crushed product (thecellulose particle size was 3 μm. The obtained crushed product and thewet acid insoluble residue described above were placed in a 90 Lpolyethylene bucket at a composition of 60 parts by weight to 40 partsby weight (dry base). Pure water was added for a total solid fractionconcentration of 25% by weight. While stirring with a 3-1 motor, themixture was neutralized with ammonia water (the pH after neutralizationwas 7.5-8.0). This was then spray dried (dispersion supply rate: 6kg/hr, inlet temperature: 180-220° C., outlet temperature: 50-70° C.),resulting in a cellulose powder T (corresponds to Example 2 of PatentDocument 1). The various physical properties of the cellulose powder Tare shown in Table 1.

Comparative Example 16

A low-speed stirrer (30LGL reactor (Commercial Name) from Ikebukuro HoroKogyo Co., Ltd.) was used with 2 kg of shredded commercially availablepulp (a natural cellulose dissolved pulp derived from wood) and 30 L of3 N aqueous hydrochloric acid. Hydrolization was performed for 24 hoursat 40° C. while stirring, resulting in acid insoluble residue. Afterthoroughly washing the obtained acid insoluble residue with pure water,the residue was filtered, resulting in a wet flock (the average particlesize of the dispersed cellulose particles in the acid insoluble residuewas 55 μm. Of the obtained wet flock, 10% by weight was further washedthoroughly with pure water, neutralized, refiltered, and air dried toproduce a dried flock. This dried flock was shredded with a home mixerand then further crushed with a jet mill (single-track jet mill STJ-200from SEISHIN ENTERPRISE CO., LTD.) to obtain a crushed product (thecellulose particle size was 3 μm.) The obtained crushed product and thewet acid insoluble residue described above were placed in a 90 Lpolyethylene bucket at a composition of 10 parts by weight to 90 partsby weight (dry base). Pure water was added for a total solid fractionconcentration of 35% by weight. While stirring with a 3-1 motor, themixture was neutralized with ammonia water (the pH after neutralizationwas 7.5-8.0). This was then spray dried (dispersion supply rate: 6kg/hr, inlet temperature: 180-220° C., outlet temperature: 50-70° C.),resulting in a cellulose powder U (corresponds to Example 5 of PatentDocument 1). The various physical properties of the cellulose powder Uare shown in Table 1.

Comparative Example 17

A low-speed stirrer (30LGL reactor (Commercial Name) from Ikebukuro HoroKogyo Co., Ltd.) was used with 2 kg of shredded commercially availablepulp (a natural cellulose kraft pulp derived from cotton linter) and 30L of 0.14 N aqueous hydrochloric acid. Hydrolization was performed for 1hour at 121° C. while stirring, resulting in acid insoluble residue.After thoroughly washing the obtained acid insoluble residue with purewater, the residue was filtered, resulting in a wet flock (the averageparticle size of the dispersed cellulose particles in the acid insolubleresidue was 36 μm. Of the obtained wet flock, 90% by weight was furtherwashed thoroughly with pure water, and then friability with a planetarymixer (the dispersed cellulose particles in the friated wet flock had anaverage particle size of 1 μm. The friated wet flock and the unfriatedwet flock were placed in a 90 L polyethylene bucket at a composition of90 parts by weight to 10 parts by weight (dry base). Pure water wasadded for a total solid fraction concentration of 30% by weight. Whilestirring with a 3-1 motor, the mixture was neutralized with ammoniawater (the pH after neutralization was 7.5-8.0). This was then spraydried (dispersion supply rate: 6 kg/hr, inlet temperature: 180-220° C.,outlet temperature: 50-70° C.), resulting in a cellulose powder V(corresponds to Example 7 of Patent Document 1). The various physicalproperties of the cellulose powder V are shown in Table 1-1 and Table1-2.

Among conventional cellulose powders, only Comparative Examples 15-17corresponding to the Examples of Patent Document 1 meet the ranges ofthe porous cellulose aggregates of the present application: the reposeangle range; the hardness range of a cylindrical molded body molded at10 MPa; and the hardness range of a cylindrical molded body molded at 20MPa the disintegration time range of a cylindrical molded body molded at20 Mpa. The advantage of the porous cellulose aggregates of the presentapplication is that the disintegration time is shorter for similarhardnesses (Example 5 and Comparative Example 15, Example 2 andComparative Example 16, and Example 3 and Comparative Example 17), thusallowing cylindrical molded bodies to be disintegrated in roughly halfthe time. This is due to the fact that, with the porous celluloseaggregates from Patent Document 1, even the larger central porediameters were approximately 1.5 μm, while the central pore diameters ofthe porous cellulose aggregates of the present application are at leastapproximately 3.0 μm. Thus, the larger central pore diameters provide afaster water permeation rate.

TABLE 1-1 Physical properties of Physical properties of Physicalproperties of powder primary cellulose cellulose dispersion Particleparticle Average Amount of Specific Media Intra- structure by FiberFiber particle fine surface Drug pore particular SEM Cellulose widththickness size particles Crystal area re- diameter pore volume(secondary powder (μm) (μm) (μm) (%) form (m²/g) activity (μm) (cm³/g)aggregation) Example 1 A 19 3 38 6 I 0.8 No 4.5 0.41 ∘ 2 B 22 2.5 38 5 I1.5 No 6.0 1.00 ∘ 3 C 22 2.5 35 9 I 1.4 No 11.0 0.55 ∘ 4 D 15 1.5 31 8 I5.0 No 8.0 0.70 ∘ 5 E 8 0.6 18 2 I 12.0 No 3.0 1.50 ∘ Comparative 1 F 398 Slurry not Slurry not I 1.4 No Not clear 0.264 x Example formed formed2 G 39 8 47 13 I 1.5 No Not clear 0.245 ∘ 3 H 39 8 49 11 I 1.7 No Notclear 0.24 ∘ 4 I 39 8 44 14 I 1 No Not clear 0.245 ∘ 5 J 39 8 37 15 I1.1 No Not clear 0.203 ∘ 6 K 39 8 Slurry not Slurry not I 5 No 2 0.5067x formed formed 7 L 0.4 0.3 1 70 I 24.1 Yes Less than 0.89 x (Median 0.1pore diameter Less than 0.1 μm) 8 M 39 8 36 15 I 1 No Not clear 0.258 ∘9 N 31 8 28 20 I 0.6 No Not clear 0.23 ∘ 10 O 39 8 33 17 I 1.9 No Notclear 0.24 ∘ 11 P 39 8 Slurry not Slurry not I 2.4 No Not clear 0.235 ∘formed formed 12 Q 39 8 Slurry not Slurry not I 0.05 No Not clear 0.048x formed formed 13 R 39 8 7 40 I 0.3 No Not clear 0.098 x 14 S 39 8 54 9I 1.2 No Not clear 0.239 x 15 T 39 8 25 30 I 12.5 No 1.5 0.82 ∘ 16 U 398 44 15 I 3.5 No 1 0.65 ∘ 17 V 0.8 0.3 5 60 I 2.2 No 0.7 0.265 ∘

TABLE 1-2 Physical properties of powder Physical properties ofcylindrical Average Apparent molded body Property to Swelling particlespecific Repose 10 MPa 20 MPa 20 MPa Cellulose disintegrate in degreesize volume angle Hardness Hardness Disintegration powder water (%) (μm)(cm³/g) (° C.) (N) (N) (Second) Example 1 A Disintegration 28.0 51 4.239 89 230 16 2 B Disintegration 10.0 230 5.1 40 95 260 10 3 CDisintegration 38.0 90 3.5 34 65 170 5 4 D Disintegration 48.0 31 3.0 2870 180 10 5 E Disintegration 6.0 150 5.5 42 145 410 30 Comparative 1 FNo disintegration 0.5 28 4.5 55 90 254 289 Example 2 G Disintegration0.0 45 5.3 51 110 309 76 3 H Disintegration 1.0 38 6.3 54 72 203 110 4 IDisintegration 0.0 105 4.4 44 66 190 35 5 J Disintegration 21.0 203 3.136 52 150 16 6 K No disintegration −4.5 174 2.1 35 45 127 245 7 L Nodisintegration −5.0 48 4.5 48 80 225 210 8 M Disintegration 19.0 49 3.244 57 161 12 9 N Disintegration 40.0 35 2 41 40 113 11 10 ODisintegration 0.0 47 5.4 56 101 188 150 11 P Disintegration 1.0 50 6.359 106 210 220 12 Q No disintegration 0.0 220 1.1 26 0 0 — 13 R Nodisintegration 1.0 93 1.3 32 5 10 — 14 S Disintegration 0.0 50 7.5 50108 280 268 15 T Disintegration 2 31 4 43 145 409 75 16 U Disintegration3 248 5 38 90 254 22 17 V Disintegration 4 190 2 26 60 169 9

Example 6 and Comparative Examples 18-28

The following were placed in a 100 L scale V-type mixer (Dalton Co.,Ltd.) and mixed for 30 minutes: 55 parts of acetaminophen (powder type,API Corporation); 0.25 parts by weight of light anhydrous silicic acid(Aerosil 200 (Commercial Name) of NIPPON AEROSIL CO., LTD.); 27 parts byweight of the cellulose powder A obtained from Example 1 or thecellulose powder B, C, E-L, and O obtained from the Comparative Examples1, 2, and 4-11, 14; 2 parts by weight of crospovidone (Kollidon CL(Commercial Name) from BASF); and 15 parts of granular lactose(Super-Tab (Commercial Name) from Lactose New Zealand). Then, 0.5 partsby weight of magnesium stearate (plant-based, made by TAIHEI CHEMICALINDUSTRIAL CO., LTD.) are added and mixed for 5 minutes to obtain aformulated powder. The total intake for the powders was 25 kg. Theformulated powder was used in a rotary tablet press (LIBRA-II(Commercial Name) from KIKUSUI SEISAKUSHO LTD, 36 stations, 410 mm turntable diameter). Pressing was performed with an 8 mm diameter, 12R punchwith a turn table speed of 50 rpm and a compression force of 7.5 kN,resulting in tablets weighing 200 mg. Tablets were sampled 60 minutesafter initiation of tablet pressing, and tablet weight, hardness,friability, and tablet pressing trouble rates were measured. Thephysical properties of the obtained tablet are shown in Table 2.

Since this formula contains a large amount of drugs with inferiorcompactibility, obtaining a hardness of 50 N or higher, the hardnessconsidered practical for tablets, is difficult. Obtaining practicaltablets is also made difficult because of the tendency for tabletpressing troubles to occur, i.e., sticking at low pressures and cappingat high pressures. Out of the Comparative Examples, the ComparativeExamples 18, 19, 26, 27, 28 provided a practical tablet hardness of 50 Nor higher, but the variation of 1.8-3.5% in tablet weight was muchhigher than the 0.8% of the Examples, making practical implementationdifficult.

TABLE 2 Physical properties of tablets that are obtained by high speedtabletting Variation of Hardness of Friability Tablet pressing Cellulosetablet weight tablet of tablet trouble rate powder (%) (N) (%) (%)Example 6 A 0.8 60 0.4 0 Comparative 18 F 2.3 65 0.6 0 Example 19 G 1.867 0.6 0 20 I 1.1 42 6.0 30 21 J 0.6 38 15.0 88 22 K 0.7 32 12.0 48 23 L1.5 48 5.0 15 24 M 1.1 35 19.0 72 25 N 0.8 30 22.7 90 26 O 2.4 55 0.9 027 P 2.3 57 0.8 0 28 S 3.5 100 0.1 0

Embodiments 7, 8 and Comparative Examples 29-39

The following were placed in a 100 L scale V-type mixer (Dalton Co.,Ltd) and mixed for 30 minutes: 40 parts of acetaminophen (powder typefrom API Corporation crushed, 6 μm average particle size); 0.5 parts byweight of light anhydrous silicic acid (Aerosil 200 (Commercial Name) ofNIPPON AEROSIL CO., LTD.); 30 parts by weight of the cellulose powder Cand D obtained from Example 3 and Example 4 and the cellulose powder G,I—P, S, and V obtained from the Comparative Examples 2, 4-11, 14 and 17;2 parts by weight of sodium croscarmellose (Kiccolate ND-2HS (CommercialName) produced by NICHIRIN CHEMICAL INDUSTRIES, LTD. and distributed byAsahi Kasei Chemicals Corporation); and 27.5 parts of granular lactose(Super-Tab (Commercial Name) from Lactose New Zealand). Then, 0.5 partsby weight external ratio of magnesium stearate (plant-based, made byTAIHEI CHEMICAL INDUSTRIAL CO., LTD.) were added and mixed for 5 minutesto obtain a formulated powder. The total intake for the powders was 2kg. The formulated powder was used in a rotary tablet press (CleanPress-12HUK (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 12 stations).Pressing was performed with an 8 mm diameter, 12R punch with a turntablespeed of 54 rpm and a compression force of 5 kN, resulting in tabletsweighing 180 mg. Tablets were sampled 10 minutes after initiation oftablet pressing, and tablet weight, hardness, friability, tabletpressing trouble rates, and disintegration times (no disk) weremeasured. The properties of the obtained tablet are shown in Table 3.

The type of drug in this formula was the same as the previous section,but the fluidity of this formula is inferior since the drug is crushed.Thus, the drug content is lower, making reduction of tablet weightvariations difficult while obtaining a practical tablet hardness of 50 Nor higher is difficult. Obtaining practical tablets is also madedifficult because of the tendency for tablet pressing troubles to occur,i.e., sticking at low pressures and capping at high pressures. Out ofthe Comparative Examples, the Comparative Examples 29, 30, 33, 36, 37,38, 39 provided a practical tablet hardness of 50 N or higher, butbesides the Comparative Example 39 the variation of 1.6-3.5% in tabletweight was much higher than the 0.2-0.50 of the Examples, makingpractical implementation difficult. With the Comparative Example 39,tablet hardness and tablet weight variations were similar to those ofthe porous cellulose aggregates of the present invention, but thedisintegration time at similar hardnesses was inferior. In direct tabletpressing, stable production can be difficult because of a tendency forthere to be differences between drug lots, especially in granularity.Thus, in terms of drug granularity it would be preferable to crush thedrugs, but in such cases the fluidity of the crushed drug is inadequate,preventing the drug content from being increased. Of the porouscellulose aggregates of the present invention, those with good fluidity,i.e., with repose angles in a low range of 25-36°, are especially usefulin overcoming this problem. Also, for drugs providing inferior tabletcompactibility, excipient must be added to provide practical hardness.Thus, the excipient itself must have good fluidity and, in order toincrease the drug content as much as possible, the excipient must have adegree of compactibility high enough that a limited amount can providepractical hardness. The porous cellulose aggregates of the presentinvention provides advantages not available in the conventionalcellulose powders in that fluidity and compactibility are both highenough to overcome the above problem.

TABLE 3 Physical properties of tablets that are obtained by high speedtabletting Variation of Hardness of Friability Tablet pressingDisintegration Cellulose tablet weight tablet of tablet trouble ratetime powder (%) (N) (%) (%) (sec) Example 7 C 0.5 52 0.5 0 11 8 D 0.2 570.3 0 15 Comparative 29 G 2.1 70 0.1 0 44 Example 30 I 1.6 50 0.4 0 3531 J 0.5 40 2.0 30 28 32 K 0.4 35 5.0 40 55 33 L 1.9 60 0.3 0 50 34 M1.5 45 0.7 0 25 35 N 0.9 29 15.0 80 23 36 O 3.1 65 0.2 0 45 37 P 3.5 680.1 0 50 38 S 2.0 69 0.1 0 59 39 V 0.2 50 0.6 0 26

Embodiment 9, 10, and Comparative Examples 40-51

The following were placed in a 5 L scale V-type mixer (Dalton Co., Ltd)and mixed for 30 minutes: 60 parts of ethenzamide (API Corporation,powder grade crushed with a compact crusher); 0.5 part by weight oflight anhydrous silicic acid (Aerosil 200 (Commercial Name) of NIPPONAEROSIL CO., LTD.); 10 parts by weight of the cellulose powder B and Eobtained from Examples 2 and 5 and the cellulose powder G, I—P, and S—Uobtained from the Comparative Examples 2, 4-11, and 14-16; 1.5 parts byweight of sodium croscarmellose (Kiccolate ND-2HS (Commercial Name)produced by NICHIRIN CHEMICAL INDUSTRIES, LTD. and distributed by AsahiKasei Chemicals Corporation); and 28 parts of granular lactose(Super-Tab (Commercial Name) from Lactose New Zealand). Then, 0.5 partby weight external ratio of magnesium stearate (plant-based, made byTAIHEI CHEMICAL INDUSTRIAL CO., LTD.) are added and mixed for 5 minutesto obtain a formulated powder. The total intake for the powders was 2kg. The formulated powder was used in a rotary tablet press (CleanPress-12HUK (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 12 stations).Pressing was performed with an 8 mm diameter, 12R punch with a turntable speed of 54 rpm and a compression force of 8 kN, resulting intablets weighing 180 mg. Tablets were sampled 10 minutes afterinitiation of tablet pressing, and tablet weight, hardness, friability,tablet pressing trouble rates, and disintegration times (no disk) weremeasured. The physical properties of the obtained tablet are shown inTable 4.

Since, in this formula, a drug hard to be soluble in water is crushed,water disintegration properties were inferior and fluidity was inferior,making it difficult to reduce variations in tablet weight. Furthermore,this formula results in tablet pressing troubles in the form of cappingat high pressures, thus making it an example of a formula in whichpractical implementation with a high drug content is difficult. Out ofthe Comparative Examples, the Comparative Examples 40, 41, 64, 47-51provided a practical tablet hardness of 50 N or higher, but thevariation of 1.6-4.0% in tablet weight was much higher than the 0.5-0.7%of the embodiments, making practical implementation difficult. With theComparative Examples 50, 51, tablet hardness and tablet weightvariations were similar to those of the porous cellulose aggregates ofthe present invention, but the disintegration time at similar hardnesseswas inferior. With lower drug solubility in water, the disintegrationtime is the rate-limiting factor, and elution time for the drug isincreased. For quick absorption in the body, quick disintegration isnecessary. As the water solubility of the drug goes lower, it is clearthat the difference in disintegration time between the porous celluloseaggregates of the present invention and the porous cellulose aggregatesof Patent Document 1 increases. Thus, the present invention is superiorto the porous cellulose aggregates of Patent Document 1 especially interms of the quick disintegration of drugs hard to be soluble in water.

TABLE 4 Physical properties of tablets that are obtained by high speedtabletting Variation of Hardness of Friability Tablet pressingDisintegration Cellulose tablet weight tablet of tablet trouble ratetime powder (%) (N) (%) (%) (sec) Example 9 B 0.5 70 0.4 0 15 10 E 0.7100 0.1 0 20 Comparative 40 G 2.3 63 0.5 0 40 Example 41 I 1.6 50 7.0 5035 42 J 0.3 44 8.0 60 20 43 K 0.2 38 13.0 80 80 44 L 1.7 64 0.6 0 75 45M 1.5 49 10.0 70 16 46 N 0.7 30 21.0 88 15 47 O 3.1 90 0.2 0 50 48 P 4.095 0.2 0 76 49 S 2.0 97 0.2 0 85 50 T 0.8 100 0.1 0 42 51 U 0.7 70 0.5 025

Embodiment 11, 12, and Comparative Examples 52-63

The following were placed in a 5 L scale V-type mixer (Dalton Co., Ltd)and mixed for 30 minutes: 55 parts of ascorbic acid (from Ebisu Co.,Ltd., crushed); 30 parts by weight of the cellulose powder B and Eobtained from Examples 2 and 5 and the cellulose powder G, I—P, and S—Uobtained from the Comparative Examples 2, 4-11, and 14-16; 1.5 parts byweight of sodium croscarmellose (Kiccolate ND-2HS (Commercial Name)produced by NICHIRIN CHEMICAL INDUSTRIES, LTD. and distributed by AsahiKasei Chemicals Corporation); and 13 parts of granular lactose(Super-Tab (Commercial Name) from Lactose New Zealand). Then, 2.0 partsby weight external ratio of magnesium stearate (plant-based, made byTAIHEI CHEMICAL INDUSTRIAL CO., LTD.) are added and mixed for 5 minutesto obtain a formulated powder. The total intake for the powders was 2kg. The formulated powder was used in a rotary tablet press (CleanPress-12HUK (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 12 stations).Pressing was performed with an 8 mm diameter, 12R punch with a turntable speed of 54 rpm and a compression force of 10 kN, resulting intablets weighing 180 mg. Tablets were sampled 10 minutes afterinitiation of tablet pressing, and tablet weight, hardness, friability,tablet pressing trouble rates, and disintegration times (no disk) weremeasured. The physical properties of the obtained tablet are shown inTable 5.

The drug used in this formula provides relatively good fluidity evenwhen crushed. However, as the drug content is increased the fluidity ofthe formula gradually decreases, thus making it more difficult to reducevariations in tablet weight when higher drug content is used. Also, thedrug used in this formula leads to tablet pressing troubles, i.e.,sticking at low pressures and capping at high pressures, making it anexample of a formula with which tablets are difficult to practicallyimplement at higher drug contents. Out of the Comparative Examples, theComparative Examples 52, 56, 59-63 provided a practical tablet hardnessof 50 N or higher, but other than the Comparative Examples 62, 63, thevariation of 1.8-2.6% in tablet weight was much higher than the 0.7-0.8%of the embodiments, making practical implementation difficult. With theComparative Examples 62, 63, tablet hardness and tablet weightvariations were similar to those of the porous cellulose aggregates ofthe present invention, but the disintegration time at similar hardnesseswas inferior. The drug used in this formula has relatively high watersolubility but water-repelling magnesium stearate must be added to avoidtablet pressing troubles. In these cases, the wettability of the tabletto water is reduced, tending to delay disintegration time even if thewater solubility of the drug is high. Especially in cases where thewettability of the tablet or the like is obstructed by an awater-repellant additive or the like in the formula, the difference indisintegration times between the porous cellulose aggregates of thepresent invention and the porous cellulose aggregates of Patent Document1 clearly increases. Thus the present invention is superior to theporous cellulose aggregates of Patent Document 1.

TABLE 5 Physical properties of tablets that are obtained by high speedtabletting Variation of Hardness of Friability Tablet pressingDisintegration Cellulose tablet weight tablet of tablet trouble ratetime powder (%) (N) (%) (%) (sec) Example 11 B 0.7 75 0.3 0 25 12 E 0.8105 0.1 0 60 Comparative 52 G 1.8 51 0.9 0 79 Example 53 I 1.2 45 2.5 565 54 J 0.6 44 5.0 30 30 55 K 0.5 40 10.0 40 110 56 L 2.1 70 0.4 0 10057 M 1.1 48 1.9 21 29 58 N 0.7 35 25.0 50 25 59 O 2.3 85 0.2 0 90 60 P2.6 88 0.3 0 105 61 S 1.9 90 0.1 0 119 62 T 0.8 105 0.1 0 90 63 U 0.7 730.5 0 35

Embodiment 13

Five grams of cellulose powder A was added to 20 g of an activecomponent solution in which an ibuprofen polyethyleneglycol solution(1:5 ratio) is diluted by 10 with ethanol (Wako Pure ChemicalIndustries, Ltd., reagent), and this was mixed in a beaker with amagnetic stirrer for 5 minutes. The resulting mixed solution was vacuumdried with an evaporator to produce a powder. A die (from KIKUSUISEISAKUSHO LTD, made with SUS 2, 3) was filled with 0.2 g of theobtained powder, and a circular flat punch (from KIKUSUI SEISAKUSHO LTD,made with SUS 2, 3) with a diameter of 0.8 cm was used to applycompression until the pressure reached 100 MPa (PCM-1A (Commercial Name)from AIKOH ENGINEERING CO., LTD. was used with a compression rate of 1cm/min). The cylindrical molded body was released after the targetpressure was maintained for 10 seconds. The surface of thecompression-molded molded body was observed and no effusion of fluidcomponents was observed. Also, 100 mL of pure water was placed in abeaker and stirred with a stirrer. A sieve with a mesh size of 1000 μmwas placed over the stirrer, and the molded body was placed on the sieveand left for one minute and observed. The results are shown in Table 6.

Comparative Example 64

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder K (corresponds to Example 2 inPatent Document 2). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

Comparative Example 65

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder L (corresponds to Example 2 inPatent Document 3). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

Comparative Example 66

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder M (corresponds to the embodimentin Patent Document 4). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

Comparative Example 67

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder N (corresponds to Example 1 inPatent Document 5). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

Comparative Example 68

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder G (corresponds to Example 5 inPatent Document 9). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

Comparative Example 69

A molded body with a fluid component was produced using operationssimilar to those from Example 13 except that the cellulose particles Awere replaced with the cellulose powder S (corresponds to Example 2 inPatent Document 10). Fluid component effusion and disintegration testswere conducted. The results are shown in Table 6.

TABLE 6 Physical properties of compression molded body CelluloseEffusion of liquid Disintegration particle components property Example13 A No effusion Disintegration Comparative K No effusion Nodisintegration Example 64 Comparative L No effusion No disintegrationExample 65 Comparative M Effusion Disintegration Example 66 ComparativeN Effusion Disintegration Example 67 Comparative G EffusionDisintegration Example 68 Comparative S No effusion No disintegrationExample 69

Embodiment 14

Cellulose particles A were used. A commercially available ibuprofen (anactive component indicated as being almost completely insoluble in wateraccording to Japanese Pharmacopeia 14) was dissolved in polyethyleneglycol (Macrogol 400 from Sanyo Kasei Co., Ltd.) at a proportion of 1:5,and then diluted by 10 with ethanol. This was added to the celluloseparticles A to result in 10% by weight. The mixture was stirred in adie. A die (from KIKUSUI SEISAKUSHO LTD, made with SUS 2, 3) was filledwith 0.2 g of the obtained powder, and a circular flat punch (fromKIKUSUI SEISAKUSHO LTD, made with SUS 2, 3) with a diameter of 0.8 cmwas used to apply compression until the pressure reached 100 MPa (PCM-1A(Commercial Name) from AIKOH ENGINEERING CO., LTD. was used with acompression rate of 1 cm/min). The cylindrical molded body was releasedafter the target pressure was maintained for 10 seconds. Fluid componenteffusion on the surface of the molded body was observed, drug elutionfrom the cylindrical molded body (elution tests were conducted with aJASCO Corporation ultraviolet absorption spectrometer at paddle speed100 rpm and 900 mL of Pharmacopeia I liquid, in which fluid absorbancewas measured and the elution rate was calculated 3 minutes after) anddisintegration time of the cylindrical molded bodies was measured. Theresults are shown in Table 7. There was no effusion of polyethyleneglycol from the cylindrical molded body, and the disintegration propertywas good with a high drug elution rate after 3 minutes, and it wasconfirmed that the dissolution was quick.

Comparative Example 70

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder K (corresponds to Example 2 in Patent Document 2).Fluid component effusion on the surface of the molded body was observed,the rate of drug elution from the cylindrical molded body was measured,and disintegratability was observed. The results are shown in Table 7.Effusion of the fluid component was not observed on the surface of thecylindrical molded body, but in the elution test the tablets did notdisintegrate in 3 minutes and floated on the liquid surface instead andthe disintegration property was poor.

Comparative Example 71

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder L (corresponds to Example 2 in Patent Document 3).Fluid component effusion on the surface of the molded body was observed,the rate of drug elution from the cylindrical molded body was measured,and disintegratability was observed. The results are shown in Table 7.Effusion of the fluid component was not observed on the surface of thecylindrical molded body, but in the elution test the tablets did notdisintegrate in 3 minutes and floated on the liquid surface instead anddisintegratability was poor.

Comparative Example 72

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder IM (corresponds to the embodiment in Patent Document4). Fluid component effusion on the surface of the molded body wasobserved, the rate of drug elution from the cylindrical molded body wasmeasured, and disintegratability was observed. The results are shown inTable 7. Effusion of the fluid component was observed on the surface ofthe cylindrical molded body, and elution tests could not be performedsince tablets could not be formed.

Comparative Example 73

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder N (corresponds to Example 1 in Patent Document 5).Fluid component effusion on the surface of the molded body was observed,the rate of drug elution from the cylindrical molded body was measured,and disintegratability was observed. The results are shown in Table 7.Effusion of the fluid component was observed on the surface of thecylindrical molded body. Tablets were not formed and elution tests couldnot be conducted.

Comparative Example 74

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder G (corresponds to Example 5 in Patent Document 9).Fluid component effusion on the surface of the molded body was observed,the rate of drug elution from the cylindrical molded body was measured,and disintegratability was observed. The results are shown in Table 7.Effusion of the fluid component was observed on the surface of thecylindrical molded body. Tablets were not formed and elution tests couldnot be conducted.

Comparative Example 75

A molded body was produced using operations similar to those fromExample 14 except that the cellulose particles A were replaced with thecellulose powder S (corresponds to Example 2 in Patent Document 10).Fluid component effusion on the surface of the molded body was observed,the rate of drug elution from the cylindrical molded body was measured,and disintegratability was observed. The results are shown in Table 7.Effusion of the fluid component was not observed on the surface of thecylindrical molded body, but disintegratability was not good, with nodisintegration in 3 minutes in the effusion test.

TABLE 7 Physical properties of compression molded body Elution rateafter Condition of Condition of 3 minutes Cellulose molded bodydisintegration (%) Example 14 A No effusion, Disintegration 97solidification Comparative K No effusion, No 35 Example 70solidification disintegration Comparative L No effusion, No 38 Example71 solidification disintegration Comparative M Effusion, not done CannotExample 72 no solidification be done Comparative N Effusion, no not doneCannot Example 73 solidification be done Comparative G Effusion, notdone Cannot Example 74 no solidification be done Comparative S Noeffusion, No 10 Example 75 solidification disintegration

Embodiment 15

A solution was formed by dissolving ethenzamide (API Corporation, powdergrade crushed with a compact crusher) in ethanol (Wako Pure ChemicalIndustries, Ltd., reagent chemical) at a proportion of 5:95. One gram ofcellulose particles A was added to 10 mL of the solution, and this wasstirred for 3 minutes with a magnetic stirrer. The resulting dispersionwas placed in an evaporator to perform complete solvent removal,resulting in a powder sample. This powder was used as in Example 14except that compression was performed at 50 MPa when forming thecylindrical molded body. An elusion test was performed. The results areshown in Table 8.

Comparative Example 76

An elution test was performed on just ethenzamide crushed according toExample 15. The results are shown in Table 8.

TABLE 8 Physical properties of compression molded body Elution rateafter 1 hour Cellulose (%) Example 15 A 100 Comparative Ethenzamide 9Example 76 material powder

Embodiment 16

Cellulose particles A were used. A commercial ibuprofen (an activecomponent indicated as being almost completely insoluble in wateraccording to Japanese Pharmacopeia 14) was dissolved in ethanol (WakoPure Chemical Industries, Ltd., reagent chemical) at a proportion of1:5, and this was added to the cellulose particles A to result in 10% byweight. The mixture was stirred in a die. The ethanol was completelyremoved from the resulting wet powder mixture using an evaporator,providing a dry powder. A die (from KIKUSUI SEISAKUSHO LTD, made withSUS 2, 3) was filled with 0.2 g of the obtained powder, and a circularflat punch (from KIKUSUI SEISAKUSHO LTD, made with SUS 2, 3) with adiameter of 0.8 cm was used to apply compression until the pressurereached 100 MPa (PCM-1A (Commercial Name) from AIKOH ENGINEERING CO.,LTD. was used with a compression rate of 1 cm/min). The cylindricalmolded body was released after the target pressure was maintained for 10seconds. One hundred of the cylindrical molded bodies were placed in abottle and sealed for 2 weeks at 40° C. Fogging on the bottle wasobserved. Also, for the obtained cylindrical molded bodies, tests wereconducted for elution of active components (elution tests were conductedwith a JASCO Corporation ultraviolet absorption spectrometer at paddlespeed 100 rpm and 900 mL of Pharmacopeia I liquid, in which fluidabsorbance was measured 1 minute after and the elution rate wascalculated 3 minutes after starting the test) and disintegrationproperty of the molded bodies was observed. The results are shown inTable 9.

Comparative Example 77

Operations similar to those of Example 16 were performed except thatcellulose particles A were replaced with cellulose powder K (correspondsto Example 2 of Patent Document 2). Clouding of bottles after sealing inthe cylindrical molded bodies was observed, elution tests wereperformed, and disintegratability was observed. The results are shown inTable 9. No clouding of bottles was observed, but the tablets did notdisintegrate in 1 minute and floated on the liquid surface instead.

Comparative Example 78

Operations similar to those of Example 16 were performed except thatcellulose particles A were replaced with cellulose powder L (correspondsto Example 2 of Patent Document 3). Clouding of bottles after sealing inthe cylindrical molded bodies was observed, elution tests wereperformed, and disintegratability was observed. The results are shown inTable 9. No clouding of bottles was observed, but the tablets did notdisintegrate in 1 minute and floated on the liquid surface instead.

Comparative Example 79

Operations similar to those of Example 16 were performed except thatcellulose particles A were replaced with cellulose powder M (correspondsto the embodiment of Patent Document 4). Clouding of bottles aftersealing in the cylindrical molded bodies was observed, elution testswere performed, and disintegratability was observed. The results areshown in Table 9. Clouding of the bottle was observed due to therecrystallization on the bottle walls of sublimated ibuprofen.

TABLE 9 Physical properties of compression molded body CelluloseCloudiness Disintegration Elution rate particle of vial property (%)Example 16 A None Disintegration 95 Comparative K None No disintegration32 Example 77 Comparative L None No disintegration 30 Example 78Comparative M Present Disintegration 18 Example 79

Embodiment 17

Twenty grams of acetaminophen (powder type, API Corporation, crushedwith a compact crusher so that the resulting acetaminophen has anaverage particle size of 16 μm and 20 g of talc (Wako Pure ChemicalIndustries, Ltd.) were placed in a polyethylene bag and mixed thoroughlyby hand for 3 minutes. In addition to this 40 g of mixed powder, thefollowing were placed in a 5 L capacity V-type mixer (Dalton Co., Ltd)and mixed for 30 minutes: 952 g of 100 mesh lactose (Pharmatose 100M(Commercial Name) from DMV Corporation); and 408 g of JapanesePharmacopeia corn starch (NIPPON STARCH CHEMICAL CO., LTD.). This wasused as a component model A having low fluidity. After 30 minutes ofmixing, the repose angle was measured to be 47°.

Next, 20 g of acetaminophen (powder type, API Corporation, crushed witha compact crusher so that the resulting acetaminophen has an averageparticle size of 16 μm and 20 g of talc (Wako Pure Chemical Industries,Ltd.) were placed in a polyethylene bag and mixed thoroughly by hand for3 minutes. In addition to this 40 g of mixed powder, the following wereplaced in a 5 L capacity V-type mixer (Dalton Co., Ltd) and mixed for 30minutes: 952 g of 100 mesh lactose (Pharmatose 100M (Commercial Name)from DMV Corporation); 408 g of Japanese Pharmacopeia corn starch(NIPPON STARCH CHEMICAL CO., LTD.); and 600 g of porous celluloseparticles A. After 30 minutes of mixing, 10 g of magnesium stearate(0.5% external ratio) was added and the result was mixed for 5 moreminutes. The repose angle was measured for the final formula powder(final composition: acetaminophen/talc/100 mesh lactose/cornstarch/porous cellulose aggregate/magnesiumstearate=1.0/1.0/47.6/20.4/30.0/0.5). The results are shown in Table 10.

The final formulated powder was used in a rotary tablet press (LIBRA-II(Commercial Name) from KIKUSUI SEISAKUSHO LTD, 36 stations, 410 mm turntable diameter). Pressing was performed with an 8 mm diameter, 12R punchwith a turn table speed of 50 rpm (108,000 tablets an hour) and acompression force of 10 kN, resulting in tablets weighing 180 mg.Tablets were sampled 10 minutes after initiation of tablet pressing, andtablet weight variation, hardness, and friability were measured. Thephysical properties of the obtained tablet are shown in Table 10.

Comparative Examples 80-83

Operations similar to those from Example 17 were performed except thatthe porous cellulose particles A were replaced with the cellulose powderK, M, N, or G. The results are shown in Table 10.

Embodiment 18

The following were placed in a 5 L scale V-type mixer (Dalton Co., Ltd)and mixed for 30 minutes: 200 g of acetaminophen (powder type, APICorporation, crushed with a compact crusher so that the resultingacetaminophen has an average particle size of 16 μm; 760 g granularlactose (SUPER-TAB (Commercial Name) made by Lactose New Zealand, soldby Asahi Kasei Chemicals Corporation); and 40 g of sodium croscarmellose(Kiccolate ND-2HS (Commercial Name) produced by NICHIRIN CHEMICALINDUSTRIES, LTD. and distributed by Asahi Kasei Chemicals Corporation).This was used as a component model B having low fluidity. After 30minutes of mixing, the repose angle was measured to be 50°.

Next, the following were placed in a 5 L capacity V-type mixer (DaltonCo., Ltd) and mixed for 30 minutes: 200 g of acetaminophen (powder type,API Corporation, crushed with a compact crusher so that the resultingacetaminophen has an average particle size of 16 μm; 760 g granularlactose (SUPER-TAB (Commercial Name) made by Lactose New Zealand, soldby Asahi Kasei Chemicals Corporation); 40 g of sodium croscarmellose(Kiccolate ND-2HS (Commercial Name) produced by NICHIRIN CHEMICALINDUSTRIES, LTD. and distributed by Asahi Kasei Chemicals Corporation);and 1000 g of porous cellulose particles A. After 30 minutes of mixing,10 g of magnesium stearate (0.5% external ratio) was added to theformula powder and the result was mixed for 5 more minutes. The reposeangle was measured for the final formula powder (final composition:acetaminophen/granular lactose/sodium croscarmellose/porous celluloseaggregate/magnesium stearate=10/38.0/2.0/50.0/0.5). The results areshown in Table 10.

Next, the final formulated powder was used in a rotary tablet press(Libra-II (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 36 stations,410 mm turn table diameter). Pressing was performed with an 8 mmdiameter, 12R punch with a turn table speed of 50 rpm (108,000 tabletsan hour) and a compression force of 10 kN, resulting in tablets weighing180 mg. Tablets were sampled 10 minutes after initiation of tabletpressing, and tablet weight variation, hardness, and friability weremeasured. The physical properties of the obtained tablet are shown inTable 10.

Comparative Examples 84-87

Operations similar to those from Example 18 were performed except thatthe porous cellulose particles A were replaced with the cellulose powderK, M, N, or G. The results are shown in Table 10.

Embodiment 19

Acetaminophen (powder type, API Corporation, crushed with a compactcrusher so that the resulting acetaminophen has an average particle sizeof 16 μm) was used as a component model C having low fluidity. Therepose angle was measured to be 55°.

Next, 200 g of acetaminophen (powder type, API Corporation, crushed witha compact crusher so that the resulting acetaminophen has an averageparticle size of 16 μm) and 18000 g of porous cellulose particles A weremixed for 30 minutes in a 5 L capacity V-type mixer (Dalton Co., Ltd).After 30 minutes of mixing, 10 g each (0.5% external ratio each) oflight anhydrous silicic acid and magnesium stearate were added to theformula powder and mixed for 5 more minutes. The repose angle wasmeasured for the final formula powder (final composition:acetaminophen/porous cellulose aggregate/light anhydrous silicicacid/magnesium stearate=10/90/0.5/0.5). The results are shown in Table10.

Next, the final formulated powder was used in a rotary tablet press(LIBRA-II (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 36 stations,410 mm turn table diameter). Pressing was performed with an 8 mmdiameter, 12R punch with a turn table speed of 50 rpm (108,000 tabletsan hour) and a compression force of 2 kN, resulting in tablets weighing180 mg. Tablets were sampled 10 minutes after initiation of tabletpressing, and tablet weight variation, hardness, and friability weremeasured. The physical properties of the obtained tablet are shown inTable 10.

Comparative Examples 88-91

Operations similar to those from Example 19 were performed except thatthe porous cellulose particles A were replaced with the cellulose powderK, M, N, or G. The results are shown in Table 10.

Out of the Comparative Examples, the Comparative Examples with apractical tablet hardness of 50 N or higher had significant variationsin tablet weight, making practical implementation difficult. The oneswith less variation in drug content in the final powder and tabletweight did not provide practical hardness, making practicalimplementation difficult.

TABLE 10 Repose angle (°) Drug content CV Component Before the additionAfter addition of value of the final Tablet weight CV Tablet hardnessCellulose model of cellulose cellulose powder (%) (N) Example 17 A A 4742 1.4 0.5 60 Comparative Example 80 K 39 3.0 0.3 32 Comparative Example81 M 46 2.0 1.1 30 Comparative Example 82 N 44 2.5 0.8 15 ComparativeExample 83 G 49 1.5 2.5 55 Example 18 A B 50 43 0.8 0.8 55 ComparativeExample 84 K 40 2.0 0.6 25 Comparative Example 85 M 47 1.6 1.8 20Comparative Example 86 N 45 1.9 1.1 9 Comparative Example 87 G 50 1.13.0 51 Example 19 A C 55 44 0.6 1.5 74 Comparative Example 88 K 42 1.81.4 40 Comparative Example 89 M 48 1.1 2.5 32 Comparative Example 90 N46 1.2 1.8 17 Comparative Example 91 G 52 0.8 3.5 56

INDUSTRIAL APPLICABILITY

A high-fluidity porous cellulose aggregate, and a compacting compositioncontaining the cellulose particles thereof and at least one type ofactive ingredient according to the present invention provides superiorcompactibility and disintegration property. In the present invention:the porous structure has a crystal structure I and an aggregation ofprimary particles; the specific surface area is in a predeterminedrange; the intraparticular pore volume is large; disintegration takesplace quickly in water; the repose angle is low. The present inventioncan be used effectively primarily in the medical field.

1. A porous cellulose aggregate having a medium pore diameter of 0.3-15μm.
 2. A porous cellulose aggregate having a medium pore diameter of3-15 μm.